Image summary: This is a photograph. The image depicts a person pouring water from a clear plastic bottle into a tall glass. The glass is partially filled with water and contains visible air bubbles, while the bottle is held horizontally by a hand. The action takes place against a blurred natural background. The image illustrates the process of hydration and the transfer of liquid from a container to a drinking vessel.

Metabolism and Nutrition

Metabolism, Nutrition, and Homeostasis

Metabolic reactions contribute to homeostasis by harvesting chemical energy from consumed nutrients for use in the body's growth, repair, and normal functioning.

The food we eat is our only source of energy for running, walking, and even breathing. Many molecules needed to maintain cells and tissues can be made from simpler precursors by the body's metabolic reactions; others—the essential amino acids, essential fatty acids, vitamins, and minerals—must be obtained from our food. As you learned in Chapter 24, carbohydrates, lipids, and proteins in food are digested by enzymes and absorbed in the digestive canal.

The products of digestion that reach body cells are monosaccharides, fatty acids, glycerol, monoglycerides, and amino acids. Some minerals and many vitamins are part of enzyme systems that catalyze the breakdown and synthesis of carbohydrates, lipids, and proteins. Food molecules absorbed by the digestive canal have three main fates:

1. Most food molecules are used to supply energy for sustaining life processes, such as active transport, D.N.A

replication, protein synthesis, muscle contraction, maintenance of body temperature, and mitosis.

2. Some food molecules serve as building blocks for the synthesis of more complex structural or functional molecules, such as muscle proteins, hormones, and enzymes.

3. Other food molecules are stored for future use. For example, glycogen is stored in liver cells, and triglycerides are stored in adipose cells.

In this chapter we discuss how metabolic reactions harvest the chemical energy stored in foods; how each group of food molecules contributes to the body's growth, repair, and energy needs; how energy balance is maintained in the body; and how body temperature is regulated. Finally, we explore some aspects of nutrition to discover why you should opt for fish instead of a burger the next time you eat out.

25.1 Metabolic Reactions

Objectives

• Define metabolism.

• Explain the role of A.T.P in anabolism and catabolism.

Metabolism metabolism; metabol-= change) refers to all of the chemical reactions that occur in the body. There are two types of metabolism: catabolism and anabolism. Those chemical reactions that break down complex organic molecules into simpler ones are collectively known as catabolism catabolism; cata-= downward).

Overall, catabolic (decomposition) reactions are exergonic; they produce more energy than they consume, releasing the chemical energy stored in organic molecules. Important sets of catabolic reactions occur in glycolysis, the Krebs cycle, and the electron transport chain, each of which will be discussed later in the chapter.

Chemical reactions that combine simple molecules and monomers to form the body's complex structural and functional components are collectively known as anabolism anabolism; ana-= upward). Examples of anabolic reactions are the formation of peptide bonds between amino acids during protein synthesis, the building of fatty acids into phospholipids that form the plasma membrane bilayer, and the linkage of glucose monomers to form glycogen. Anabolic reactions are endergonic; they consume more energy than they produce.

Metabolism is an energy-balancing act between catabolic (decomposition) reactions and anabolic (synthesis) reactions. The molecule that participates most often in energy exchanges in living cells is A.T.P (adenosine triphosphate), which couples energy-releasing catabolic reactions to energy-requiring anabolic reactions.

The metabolic reactions that occur depend on which enzymes are active in a particular cell at a particular time, or even in a particular part of the cell. Catabolic reactions can be occurring in the mitochondria of a cell at the same time as anabolic reactions are taking place in the endoplasmic reticulum.

A molecule synthesized in an anabolic reaction has a limited lifetime. With few exceptions, it will eventually be broken down and its component atoms recycled into other molecules or excreted from the body. Recycling of biological molecules occurs continuously in living tissues, more rapidly in some than in others. Individual cells may be refurbished molecule by molecule, or a whole tissue may be rebuilt cell by cell.

Coupling of Catabolism and Anabolism by A.T.P

The chemical reactions of living systems depend on the efficient transfer of manageable amounts of energy from one molecule to another. The molecule that most often performs this task is A.T.P, the “energy currency” of a living cell. Like money, it is readily available to “buy” cellular activities; it is spent and earned over and over. A typical cell has about a billion molecules of A.T.P, each of which typically lasts for less than a minute before being used. Thus, A.T.P is not a long-term storage form of currency, like gold in a vault, but rather convenient cash for moment-to-moment transactions.

Recall from Chapter 2 that a molecule of A.T.P consists of an adenine molecule, a ribose molecule, and three phosphate groups bonded to one another (see Figure 2.26). Figure 25.1 shows how A.T.P links anabolic and catabolic reactions. When the terminal phosphate group is split off A.T.P, adenosine diphosphate (A.D.P) and a phosphate group (symbolized as P) are formed. Some of the energy released is used to drive anabolic reactions such as the formation of glycogen from glucose. In addition, energy from complex molecules is used in catabolic reactions to combine A.D.P and a phosphate group to resynthesize A.T.P:

Figure 25.1 summary: This is a conceptual diagram illustrating a biochemical cycle. The figure depicts the relationship between catabolic and anabolic reactions, showing how energy is cycled between adenosine triphosphate and adenosine diphosphate. Catabolic reactions break down complex molecules into simple molecules, releasing heat and transferring energy to synthesize ATP. Conversely, anabolic reactions use energy from ATP to build complex molecules from simple ones, also releasing heat. The diagram concludes that metabolism is a continuous cycle where catabolism provides the energy necessary for anabolism, maintaining a balance between the synthesis and breakdown of organic molecules.

Math summary: This process describes the resynthesis of adenosine triphosphate. It combines adenosine diphosphate, a phosphate group, and an input of energy to produce the final output of adenosine triphosphate.

About 40% of the energy released in catabolism is used for cellular functions; the rest is converted to heat, some of which helps maintain normal body temperature. Excess heat is lost to the environment. Compared with machines, which typically convert only 10 to 20% of energy into work, the 40% efficiency of the body's metabolism is impressive. Still, the body has a continuous need to take in and process external sources of energy so that cells can synthesize enough A.T.P to sustain life.

Figure 25.1 Role of A.T.P in Linking Anabolic and Catabolic

reactions. When complex molecules and polymers are split apart (catabolism, at left), some of the energy is transferred to form A.T.P and the rest is given off as heat. When simple molecules and monomers are combined to form complex molecules (anabolism, at right), A.T.P provides the energy for synthesis, and again some energy is given off as heat.

The coupling of energy-releasing and energy-requiring reactions is achieved through A.T.P.

Q In a pancreatic cell that produces digestive enzymes, does anabolism or catabolism predominate?

1. What is metabolism? Distinguish between anabolism and catabolism, and give examples of each.

2. How does A.T.P link anabolism and catabolism?

25.2 Energy Transfer

Objectives

• Describe oxidation-reduction reactions.

• Explain the role of A.T.P in metabolism.

Various catabolic reactions transfer energy into the “high-energy” phosphate bonds of A.T.P. Although the amount of energy in these bonds is not exceptionally large, it can be released quickly and easily. Before discussing metabolic pathways, it is important to understand how this transfer of energy occurs. Two important aspects of energy transfer are oxidation-reduction reactions and mechanisms of A.T.P generation.

Oxidation-Reduction Reactions

Oxidation (ok'-si-DÃ-shun) is the removal of electrons from an atom or molecule; the result is a decrease in the potential energy of the atom or molecule. Because most biological oxidation reactions involve the loss of hydrogen atoms, they are called dehydrogenation reactions. An example of an oxidation reaction is the conversion of lactic acid into pyruvic acid:

Math summary: This process performs an oxidation reaction to convert lactic acid into pyruvic acid. The computation removes two hydrogen atoms from the input molecule to produce the final output.

In the preceding reaction, 2 H (H⁺ + H⁻) means that two neutral hydrogen atoms (2 H) are removed as one hydrogen ion (H⁺) plus one hydride ion (H⁻).

Reduction reduction is the opposite of oxidation; it is the addition of electrons to a molecule. Reduction results in an increase in the potential energy of the molecule. An example of a reduction reaction is the conversion of pyruvic acid into lactic acid:

Image summary: This figure is a chemical reaction diagram. It illustrates the chemical transformation of pyruvic acid into lactic acid through a reduction process, which involves the addition of hydrogen ions and hydride ions. The diagram indicates that the carbonyl group in pyruvic acid is converted into a hydroxyl group in lactic acid, demonstrating that pyruvic acid acts as the precursor and lactic acid as the resulting product of this specific reduction reaction.

When a substance is oxidized, the liberated hydrogen atoms do not remain free in the cell but are transferred immediately by coenzymes to another compound. Two coenzymes are commonly used by animal cells to carry hydrogen atoms: nicotinamide adenine dinucleotide (N.A.D), a derivative of the B vitamin niacin, and flavin adenine dinucleotide (F.A.D), a derivative of vitamin B₂ (riboflavin). The oxidation and reduction states of N.A.D⁺ and F.A.D can be represented as follows:

Math summary: This process describes the reduction of coenzymes where oxidized nicotinamide adenine dinucleotide and flavin adenine dinucleotide act as inputs. Each coenzyme accepts two hydrogen atoms to produce reduced outputs known as NADH and FADH two.

When N.A.D⁺ is reduced to N.A.D.H + H⁺, the N.A.D⁺ gains a hydride ion (H⁺), neutralizing its charge, and the H⁺ is released into the surrounding solution. When N.A.D.H is oxidized to N.A.D⁺, the loss of the hydride ion results in one less hydrogen atom and an additional positive charge. F.A.D is reduced to F.A.D.H₂ when it gains a hydrogen ion and a hydride ion, and F.A.D.H₂ is oxidized to F.A.D when it loses the same two ions.

Oxidation and reduction reactions are always coupled; each time one substance is oxidized, another is simultaneously reduced. Such paired reactions are called oxidation–reduction or redox reactions. For example, when lactic acid is oxidized to form pyruvic acid, the two hydrogen atoms removed in the reaction are used to reduce N.A.D ^{+} . This coupled redox reaction may be written as follows:

Image summary: This figure is a biochemical pathway diagram. It illustrates the interconversion between lactic acid and pyruvic acid, coupled with the conversion of nicotinamide adenine dinucleotide (NAD+) and NADH. The diagram shows that lactic acid, in its reduced state, is converted into pyruvic acid in its oxidized state, while simultaneously NAD+ in its oxidized state is converted into NADH and a hydrogen ion in their reduced states. It can be inferred that this process represents a redox reaction where the oxidation of lactic acid is coupled with the reduction of NAD+.

An important point to remember about oxidation-reduction reactions is that oxidation is usually an exergonic (energy-releasing) reaction. Cells use multistep biochemical reactions to release energy from energy-rich, highly reduced compounds (with many hydrogen atoms) to lower energy, highly oxidized compounds (with many oxygen atoms or multiple bonds). For example, when a cell oxidizes a molecule of glucose ( C 6 H 12 O 6 ), the energy in the glucose molecule is removed in a stepwise manner.

Ultimately, some of the energy is captured by transferring it to A.T.P, which then serves as an energy source for energy-requiring reactions within the cell. Compounds with many hydrogen atoms such as glucose contain more chemical potential energy than oxidized compounds. For this reason, glucose is a valuable nutrient.

Mechanisms of A.T.P Generation

Some of the energy released during oxidation reactions is captured within a cell when A.T.P is formed. Briefly, a phosphate group phosphate is added to A.D.P, with an input of energy, to form A.T.P. The two high-energy phosphate bonds that can be used to transfer energy are indicated by squiggles (tilde):

Adenosine plus phosphate plus phosphate plus energy yields A.D.P Adenosine — ☐ ~ ☐ ~ ☐ A.T.P The high-energy phosphate bond that attaches the third phosphate group contains the energy stored in this reaction. The addition of a phosphate group to a molecule, called phosphorylation phosphorylation, increases its potential energy. Organisms use three mechanisms of phosphorylation to generate A.T.P:

1. Substrate-level phosphorylation generates A.T.P by transferring a high-energy phosphate group from an intermediate phosphorylated metabolic compound—a substrate—directly to A.D.P. In human cells, this process occurs in the cytosol.

2. Oxidative phosphorylation removes electrons from organic compounds and passes them through a series of electron acceptors, called the electron transport chain, to molecules of oxygen ( O 2 ). This process occurs in the inner mitochondrial membrane of cells.

3. Photophosphorylation occurs only in chlorophyll-containing plant cells or in certain bacteria that contain other light-absorbing pigments.

Checkpoint

3. How is a hydride ion different from a hydrogen ion? What is the involvement of both ions in redox reactions?

4. What are three ways that A.T.P can be generated?

25.3 Carbohydrate Metabolism

Objective

- Describe the fate, metabolism, and functions of carbohydrates.

As you learned in Chapter 24, both polysaccharides and disaccharides are hydrolyzed into the monosaccharides glucose (about 80%), fructose, and galactose during the digestion of carbohydrates. (Some fructose is converted into glucose as it is absorbed through the intestinal epithelial cells.) Hepatocytes (liver cells) convert most of the remaining fructose and practically all of the galactose to glucose. So the story of carbohydrate metabolism is really the story of glucose metabolism. Because negative feedback systems maintain blood glucose at about 90 milligrams/100 mL of plasma (5 millimoles/liter), a total of 2 to 3 g of glucose normally circulates in the blood.

The Fate of Glucose

Because glucose is the body's preferred source for synthesizing A.T.P, its use depends on the needs of body cells, which include the following:

• A.T.P production. In body cells that require immediate energy, glucose is oxidized to produce A.T.P. Glucose not needed for immediate A.T.P production can enter one of several other metabolic pathways.

• Amino acid synthesis. Cells throughout the body can use glucose to form several amino acids, which then can be incorporated into proteins.

• Glycogen synthesis. Hepatocytes and muscle fibers can perform glycogenesis glycogenesis; glyco-= sugar or sweet; -genesis = to generate), in which hundreds of glucose monomers are combined to form the polysaccharide glycogen. Total storage capacity of glycogen is about 125 g in the liver and 375 g in skeletal muscles.

• Triglyceride synthesis. When the glycogen storage areas are filled up, hepatocytes can transform the glucose to glycerol and fatty acids that can be used for lipogenesis lipogenesis, the synthesis of triglycerides. Triglycerides then are deposited in adipose tissue, which has virtually unlimited storage capacity.

Glucose Movement into Cells

Before glucose can be used by body cells, it must first pass through the plasma membrane and enter the cytosol. Glucose absorption in the digestive canal (and kidney tubules) is accomplished via secondary active transport ( Na superscript plus -glucose symporters). Glucose entry into most other body cells occurs via GluT molecules, a family of transporters that bring glucose into cells via facilitated diffusion (see Section 3.3). A high level of insulin increases the insertion of one type of GluT, called Glu T 4, into the plasma membranes of most body cells, thereby increasing the rate of facilitated diffusion of glucose into cells.

In neurons and hepatocytes, however, another type of GluT is always present in the plasma membrane, so glucose entry is always “turned on.” On entering a cell, glucose becomes phosphorylated. Because GluT cannot transport phosphorylated glucose, this reaction traps glucose within the cell.

Glucose Catabolism

The oxidation of glucose to produce A.T.P is also known as cellular respiration, and it involves four sets of reactions: glycolysis, Figure 25.2 Overview of cellular respiration (oxidation of glucose). A modified version of this figure appears in several places in this chapter to indicate the relationships of particular reactions to the overall process of cellular respiration.

Figure 25.2 summary: This figure is a biological process diagram. It illustrates the stages of cellular respiration, starting from glucose and progressing through glycolysis, the formation of acetyl coenzyme A, the Krebs cycle, and ending with the electron transport chain. The diagram tracks the flow of molecules, the release of carbon dioxide, and the production of energy carriers such as ATP, NADH, and FADH2. The process demonstrates that while initial stages produce a small amount of energy, the majority of ATP is generated during the final stage through the electron transport chain, which utilizes oxygen to produce water as a byproduct.

The oxidation of glucose involves glycolysis, the formation of acetyl coenzyme A, the Krebs cycle, and the electron transport chain. the formation of acetyl coenzyme A, the Krebs cycle, and the electron transport chain (Figure 25.2). ① Glycolysis. A set of reactions in which one glucose molecule is oxidized and two molecules of pyruvic acid are produced. The reactions also produce two molecules of A.T.P and two energy-containing N.A.D.H + H ^{+} .

2 Formation of acetyl coenzyme A. A transition step that prepares pyruvic acid for entrance into the Krebs cycle. This step also produces energy-containing N.A.D.H + H⁺ plus carbon dioxide (C-O₂).

3 Krebs cycle reactions. These reactions oxidize acetyl coenzyme A and produce C-O₂, A.T.P, N.A.D.H + H⁺, and F.A.D.H₂.

Electron transport chain reactions. These reactions oxidize N.A.D.H + H⁺ and F.A.D.H₂ and transfer their electrons through a series of electron carriers.

Because glycolysis does not require oxygen, it can occur under aerobic (with oxygen) or anaerobic (without oxygen) conditions. By contrast, the reactions of the Krebs cycle and electron transport chain require oxygen and are collectively referred to as aerobic respiration. Thus, when oxygen is present, all four phases occur: glycolysis, formation of acetyl coenzyme A, the Krebs cycle, and the electron transport chain. However, if oxygen is not available or at a low concentration, pyruvic acid is converted to a substance called lactic acid (see Figure 25.5) and the remaining steps of cellular respiration do not occur. When glycolysis occurs by itself under anaerobic conditions, it is referred to as anaerobic glycolysis.

Figure 25.5 summary: This figure is a biological pathway diagram. It illustrates the metabolic fate of glucose, starting with glycolysis in the cytosol which produces pyruvic acid. The diagram shows a divergence where pyruvic acid can either enter an anaerobic pathway to produce lactic acid or an aerobic pathway leading into the mitochondrion. Inside the mitochondrial matrix, pyruvic acid undergoes decarboxylation mediated by pyruvate dehydrogenase to form acetyl coenzyme A, releasing carbon dioxide and reducing NAD+ to NADH. The final conclusion is that under aerobic conditions, pyruvic acid is converted into acetyl coenzyme A, which then enters the Krebs cycle for further energy production.

Glycolysis During glycolysis glycolysis; -lysis = breakdown), chemical reactions split a 6-carbon molecule of glucose into two 3-carbon molecules of pyruvic acid (Figure 25.3). Even though glycolysis consumes two A.T.P molecules, it produces four A.T.P molecules, for a net gain of two A.T.P molecules for each glucose molecule that is oxidized.

Figure 25.3 summary: This figure consists of two schematic diagrams illustrating metabolic pathways. The first part provides a high-level overview of cellular respiration, tracing the flow of energy from glucose through glycolysis, the formation of acetyl coenzyme A, the Krebs cycle, and the electron transport chain. The second part provides a detailed map of the glycolysis process, showing the breakdown of a single glucose molecule into pyruvic acid through several intermediate stages, including dihydroxyacetone phosphate and glyceraldehyde 3-phosphate. The diagrams illustrate that cellular respiration is a multi-stage process that converts chemical energy from glucose into usable cellular energy. Glycolysis serves as the initial step, occurring before the products enter the Krebs cycle and the electron transport chain. The detailed glycolysis pathway shows that while some energy is consumed initially to prime the glucose molecule, a greater amount of energy is recovered in the later stages of the process. It can be inferred that the electron transport chain is the final and most productive stage of cellular respiration, as it utilizes oxygen to produce a significant amount of energy. Furthermore, the glycolysis overview demonstrates that the process is symmetrical, splitting the original glucose molecule into two identical three-carbon pyruvic acid molecules, each contributing to the overall energy yield.

Figure 25.4 shows the 10 reactions that glycolysis comprises. In the first half of the sequence (reactions 1 through 5 ), energy in the form of A.T.P is “invested” and the 6-carbon glucose is split into two 3-carbon molecules of glyceraldehyde 3-phosphate. Phosphofructokinase (fos'-fó-fruk'-to-Ki-nas), the enzyme that catalyzes step 3 , is the key regulator of the rate of glycolysis. The activity of this enzyme is high when A.D.P concentration is high, in which case A.T.P is produced rapidly. When the activity of phosphofructokinase is low, most glucose does not enter the reactions of glycolysis but instead undergoes conversion to glycogen for storage. In the second half of the sequence (reactions 6 through 10 ), the two glyceraldehyde 3-phosphate molecules are converted to two pyruvic acid molecules and A.T.P is generated.

Figure 25.4 summary: This figure is a biochemical pathway diagram. It illustrates the step-by-step sequence of chemical reactions in glycolysis, showing the transformation of glucose into pyruvate through various intermediate molecules. The diagram details the enzymatic steps, the consumption and production of energy carriers, and the splitting of a six-carbon sugar into two three-carbon molecules. The process demonstrates that glucose undergoes phosphorylation and isomerization before being cleaved into two glyceraldehyde-3-phosphate molecules. These intermediates are then oxidized and phosphorylated to eventually yield pyruvate, resulting in a net gain of energy in the form of ATP and NADH.

The Fate of Pyruvic Acid The fate of pyruvic acid produced during glycolysis depends on the availability of oxygen During glycolysis, each molecule of glucose is converted to two molecules of pyruvic acid.

(Figure 25.5). If oxygen is scarce (anaerobic conditions)—for example, in skeletal muscle fibers during strenuous exercise—then pyruvic acid is reduced via an anaerobic pathway by the addition of two hydrogen atoms to form lactic acid (lactate):

Math summary: This chemical equation describes the reduction of pyruvic acid into lactic acid. The process combines pyruvic acid with nicotinamide adenine dinucleotide and hydrogen ions to produce lactic acid and regenerate oxidized nicotinamide adenine dinucleotide.

This reaction regenerates the N.A.D superscript plus that was used in the oxidation of glyceraldehyde 3-phosphate (see step {6} in Figure 25.4) and thus allows glycolysis to continue. As lactic acid is produced, it rapidly diffuses out of the cell and enters the blood. Hepatocytes remove lactic acid from the blood and convert it back to pyruvic acid. Recall that a buildup of lactic acid is one factor that contributes to muscle fatigue.

When oxygen is plentiful (aerobic conditions), most cells convert pyruvic acid to acetyl coenzyme A. This molecule links glycolysis, which occurs in the cytosol, with the Krebs cycle, which occurs in the matrix of mitochondria. Pyruvic acid enters the mitochondrial matrix with the help of a special transporter protein. Because they lack mitochondria, red blood cells can only produce A.T.P through glycolysis.

Formation of Acetyl Coenzyme A Each step in the oxidation of glucose requires a different enzyme, and often a coenzyme as well. The coenzyme used at this point in cellular respiration is coenzyme A (CoA), which is derived from panto-thenic acid, a B vitamin. During the transitional step between glycolysis and the Krebs cycle, pyruvic acid is prepared for entrance into the cycle. The enzyme pyruvate dehydrogenase pyruvate de-Hi-dro-jen-as), which is located exclusively in the mitochondrial matrix, converts pyruvic acid to a 2-carbon fragment called an acetyl group acetyl by removing a molecule of carbon dioxide (Figure 25.5). The loss of a molecule of C-O₂ by a substance is called decarboxylation decarboxylation. This is the first reaction in cellular respiration that Figure 25.4 The 10 reactions of glycolysis. 1 Glucose is phosphorylated, using a phosphate group from an A.T.P molecule to form glucose 6-phosphate. 2 Glucose 6-phosphate is converted to fructose 6-phosphate. 3 A second A.T.P is used to add a second phosphate group to fructose 6-phosphate to form fructose 1,6-bisphosphate. 4 and 5 Fructose splits into two 3-carbon molecules, glyceraldehyde 3-phosphate (G 3 P and dihydroxyacetone phosphate, each having one phosphate group. 6 Oxidation occurs as two molecules of N.A.D⁺ accept two pairs of electrons and hydrogen ions from two molecules of G 3 P to form two molecules of N.A.D.H. Body cells use the two N.A.D.H produced in this step to generate A.T.P in the electron transport chain. A second phosphate group attaches to G 3 P, forming 1,3-bisphosphoglyceric acid B.P.G. 7 through 10 These reactions generate four molecules of A.T.P and produce two molecules of pyruvic acid (pyruvate*). *The carboxyl groups ( C.O.O.H ) of intermediates in glycolysis and in the citric acid cycle are mostly ionized at the pH of body fluids to C.O.O superscript minus . The suffix “-ic acid” indicates the non-ionized form, whereas the ending “-ate” indicates the ionized form. Although the “-ate” names are more correct, we will use the “acid” names because these terms are more familiar.

When oxygen is plentiful, pyruvic acid enters mitochondria, is converted to acetyl coenzyme A, and enters the Krebs cycle (aerobic pathway). When oxygen is scarce, most pyruvic acid is converted to lactic acid via an anaerobic pathway. releases carbon dioxide. During this reaction, pyruvic acid is also oxidized. Each pyruvic acid loses two hydrogen atoms in the form of one hydride ion (H minus) plus one hydrogen ion (H plus). The coenzyme N.A.D plus is reduced as it picks up the H minus from pyruvic acid; the H plus is released into the mitochondrial matrix. The reduction of N.A.D plus to N.A.D.H plus H plus is indicated in Figure 25.5 by the curved arrow entering and then leaving the reaction. Recall that the oxidation of one glucose molecule produces two molecules of pyruvic acid, so for each molecule of glucose, two molecules of carbon dioxide are lost and two N.A.D.H + H⁺ are produced. The acetyl group attaches to coenzyme A, producing a molecule called acetyl coenzyme A (acetyl CoA).

The Krebs Cycle Once the pyruvic acid has undergone decarboxylation and the remaining acetyl group has attached to CoA, the resulting compound (acetyl CoA) is ready to enter the Krebs cycle (Figure 25.6). The Krebs cycle—named for the biochemist Hans Krebs, who described these reactions in the 1930s—is also known as the citric acid cycle, for the first molecule formed when an acetyl group joins the cycle. The reactions occur in the mitochondrial matrix and consist of a series of oxidation-reduction reactions and decarboxylation reactions that release C-O₂. In the Krebs cycle, the oxidation-reduction reactions transfer chemical energy, in the form of electrons, to two coenzymes—N.A.D⁺ and F.A.D. The pyruvic acid derivatives are oxidized, and the coenzymes are reduced. In addition, one step generates A.T.P. Figure 25.7 shows the reactions of the Krebs cycle in more detail.

Figure 25.6 summary: This figure consists of two conceptual diagrams illustrating biological processes. The first part provides a high-level flow of cellular respiration, depicting the sequential stages of glycolysis, the formation of acetyl coenzyme A, the Krebs cycle, and the electron transport chain. It shows the conversion of glucose into pyruvic acid and eventually into water, highlighting the production of energy carriers and carbon dioxide at various stages. The second part provides a detailed overview of the Krebs cycle, showing the transformation of pyruvic acid into acetyl coenzyme A and its subsequent entry into a cyclic series of reactions. Inferences from the figure indicate that cellular respiration is a multi-step process that extracts energy from glucose through a series of oxidative reactions. The Krebs cycle specifically acts as a central hub that generates multiple electron carriers and carbon dioxide, which then feed into the electron transport chain to produce a larger yield of energy.

Figure 25.7 summary: This figure is a biochemical pathway diagram. It illustrates the Krebs cycle, starting from the conversion of pyruvic acid to acetyl coenzyme A and following the sequential chemical transformations of various organic acids. The diagram details the cyclical process where oxaloacetic acid combines with acetyl coenzyme A to form citric acid, which then undergoes a series of reactions to regenerate oxaloacetic acid. The process shows the release of carbon dioxide and the reduction of electron carriers, specifically the conversion of NAD+ to NADH and FAD to FADH2, as well as the production of energy molecules like ATP and GTP. It can be inferred that the Krebs cycle serves as a central metabolic hub that oxidizes carbon-based molecules to harvest high-energy electrons for the electron transport chain and generates a small amount of immediate chemical energy.

Each time that an acetyl CoA molecule enters the Krebs cycle, the cycle undergoes one complete “turn,” starting with the production of citric acid and ending with the formation of oxaloacetic acid (Figure 25.7). For each turn of the Krebs cycle, three N.A.D.H, three H⁺, and one F.A.D.H₂ are produced by oxidation-reduction reactions, and one molecule of A.T.P is generated by substrate-level phosphorylation. Because each glucose molecule provides two acetyl CoA molecules, there are two turns of the Krebs cycle per molecule of glucose catabolized. This results in the production of six molecules of N.A.D.H, six H⁺, and two molecules of F.A.D.H₂ by oxidation-reduction reactions, and two molecules of A.T.P by substrate-level phosphorylation.

The formation of N.A.D.H and F.A.D.H₂ is the most important outcome of the Krebs cycle because these reduced coenzymes contain the energy originally stored in glucose and then in pyruvic acid. They will later yield many molecules of A.T.P from the electron transport chain.

Liberation of C-O 2 occurs as pyruvic acid is converted to acetyl CoA and during the two decarboxylation reactions of the Krebs cycle (see Figure 25.6). Because each molecule of glucose generates two molecules of pyruvic acid, six molecules of C-O 2 are liberated from each original glucose molecule catabolized along this pathway. The molecules of C-O 2 diffuse out of the mitochondria, through the cytosol and plasma membrane, and then into the blood. Blood transports the C-O 2 to the lungs, where it eventually is exhaled.

The Electron Transport Chain The electron transport chain is a series of electron carriers, integral membrane proteins in the inner mitochondrial membrane. This membrane is folded into cristae that increase its surface area, accommodating thousands of copies of the transport chain in each mitochondrion. Each carrier in the chain is reduced as it picks up electrons and oxidized as it gives up electrons. As electrons pass through the chain, a series of exergonic reactions release small amounts of energy; this energy is used to Figure 25.6 After formation of acetyl coenzyme A, the next stage of cellular respiration is the Krebs cycle. form A.T.P. In cellular respiration, the final electron acceptor of the chain is oxygen. Because this mechanism of A.T.P generation links chemical reactions (the passage of electrons along the transport chain) with the pumping of hydrogen ions, it is called chemiosmosis (kem'-e-oz-Mo-sis; chemi-= chemical; -osmosis = pushing). Together, chemiosmosis and the electron transport chain constitute oxidative phosphorylation.

Briefly, chemiosmosis works as follows (Figure 25.8):

Figure 25.8 summary: This figure is a biological diagram. It illustrates the process of chemiosmosis within the inner mitochondrial membrane, showing the relationship between the electron transport chain, the movement of hydrogen ions, and the production of ATP. The diagram depicts energy from NADH powering proton pumps to move hydrogen ions from the mitochondrial matrix into the intermembrane space, creating a concentration gradient. These ions then flow back into the matrix through an ATP synthase channel. It can be inferred that the electron transport chain establishes a high concentration of hydrogen ions outside the matrix, and the subsequent diffusion of these ions back into the matrix provides the necessary energy for ATP synthase to convert ADP and inorganic phosphate into ATP.

- ① Energy from N.A.D.H + H⁺ passes along the electron transport chain and is used to pump H⁺ from the mitochondrial matrix into the space between the inner and outer mitochondrial membranes. This mechanism is called a proton pump because H⁺ ions consist of a single proton.

- ② A high concentration of H ^{+} accumulates between the inner and outer mitochondrial membranes.

- ③ A.T.P synthesis then occurs as hydrogen ions flow back into the mitochondrial matrix through a special type of H ^{+} channel in the inner membrane.

Electron Carriers Several types of molecules and atoms serve as electron carriers:

• Flavin mononucleotide (F.M.N) flavin mononucleotide is a flavoprotein derived from riboflavin (vitamin

• Cytochromes (Sî-tô-krômz) are proteins with an iron-containing group (heme) capable of existing alternately in a reduced form (Fe²⁺) and an oxidized form (Fe³⁺). The cytochromes involved in the electron transport chain include cytochrome b (cyt b), cytochrome c₁ (cyt c₁), cytochrome c (cyt c), cytochrome a (cyt a), and cytochrome

• Iron-sulfur (Fe-S) centers contain either two or four iron atoms bound to sulfur atoms that form an electron transfer center within a protein.

- Copper (Cu) atoms bound to two proteins in the chain also participate in electron transfer.

• Coenzyme Q (Q), is a nonprotein, low-molecular-weight carrier that is mobile in the lipid bilayer of the inner membrane.

Figure 25.7 The eight reactions of the Krebs cycle. 1 Entry of the acetyl group. The chemical bond that attaches the acetyl group to coenzyme A (CoA) breaks, and the 2-carbon acetyl group attaches to a 4-carbon molecule of oxaloacetic acid to form a 6-carbon molecule called citric acid. CoA is free to combine with another acetyl group from pyruvic acid and repeat the process. 2 Isomerization. Citric acid undergoes isomerization to isocitric acid, which has the same molecular formula as citrate. Notice, however, that the hydroxyl group O.H is attached to a different carbon. 3 Oxidative decarboxylation. Isocitric acid is oxidized and loses a molecule of C-O₂, forming alpha-ketoglutaric acid.

The H⁺ from the oxidation is passed on to N.A.D⁺, which is reduced to N.A.D.H + H⁺. 4 Oxidative decarboxylation. Alpha-ketoglutaric acid is oxidized, loses a molecule of C-O₂, and picks up CoA to form succinyl-CoA. 5 Substrate-level phosphorylation. CoA is displaced by a phosphate group, which is then transferred to guanosine diphosphate G.D.P to form guanosine triphosphate (G.T.P). G.T.P can donate a phosphate group to A.D.P to form A.T.P. 6 Dehydrogenation. Succinic acid is oxidized to fumaric acid as two of its hydrogen atoms are transferred to the coenzyme flavin adenine dinucleotide (F.A.D), which is reduced to F.A.D.H₂. 7 Hydration. Fumaric acid is converted to malic acid by the addition of a molecule of water. 8 Dehydrogenation. In the final step in the cycle, malic acid is oxidized to re-form oxaloacetic acid. Two hydrogen atoms are removed and one is transferred to N.A.D⁺, which is reduced to N.A.D.H + H⁺. The regenerated oxaloacetic acid can combine with another molecule of acetyl CoA, beginning a new cycle.

The three main results of the Krebs cycle are the production of reduced coenzymes (N.A.D.H and F.A.D.H 2 ), which contain stored energy; the generation of G.T.P, a high-energy compound that is used to produce A.T.P; and the formation of C-O 2 , which is transported to the lungs and exhaled.

Figure 25.8 Chemiosmosis.

Steps in Electron Transport and Chemiosmotic A.T.P

Generation Within the inner mitochondrial membrane, the carriers of the electron transport chain are clustered into three complexes, each of which acts as a proton pump that expels H superscript plus from the mitochondrial matrix and helps create an electrochemical gradient of H superscript plus . Each of the three proton pumps transports electrons and pumps H superscript plus , as shown in Figure 25.9. Notice that oxygen is used to help form water in step ③. This is the only point in aerobic cellular respiration where O 2 is consumed. Cyanide is a deadly poison because it binds to the cytochrome oxidase complex and blocks this last step in electron transport.

The pumping of H⁺ produces both a concentration gradient of protons and an electrical gradient. The buildup of H⁺ makes one side of the inner mitochondrial membrane positively charged compared with the other side. The resulting electrochemical gradient has potential energy, called the proton motive force.

Proton channels in the inner mitochondrial membrane allow H⁺ to flow back across the membrane, driven by the proton motive force. As H⁺ flow back, they generate A.T.P because the H⁺ channels also include an enzyme called A.T.P synthase synthase. The enzyme uses the proton motive force to synthesize A.T.P from A.D.P and P. The process of chemiosmosis is responsible for most of the A.T.P produced during cellular respiration.

For every molecule of N.A.D.H + H⁺ that drops off hydrogen atoms to the electron transport chain, two or three molecules of A.T.P (average = 2.5) are produced via oxidative phosphorylation. For every molecule of F.A.D.H₂ that drops off hydrogen atoms to the electron transport chain, only one or two molecules of A.T.P (average = 1.5) are produced via oxidative phosphorylation. This is due to the fact that F.A.D.H 2 drops off its hydrogen atoms at a lower step along the electron transport chain than N.A.D.H + H superscript plus .

Summary of Cellular Respiration The various electron transfers in the electron transport chain generate either 26 or 28 A.T.P molecules from each molecule of glucose that is catabolized: either 23 or 25 from the 10 molecules of N.A.D.H + H⁺ and three from the two molecules of F.A.D.H₂. The discrepancy in the number of A.T.P formed from N.A.D.H + H⁺ via oxidative phosphorylation is due to the fact that the two N.A.D.H + H⁺ molecules produced in the cytosol during glycolysis cannot enter mitochondria. Instead they donate their electrons to one of two transfer shuttles, known as the malate shuttle and the glycerol phosphate shuttle. In cells of the liver, kidneys, and heart, use of the malate shuttle results in an average of 2.5 molecules of A.T.P synthesized for each molecule of N.A.D.H + H⁺. In other body cells, such as skeletal muscle fibers and neurons, use of the glycerol phosphate shuttle results in an average of 1.5 molecules of A.T.P synthesized for each molecule of N.A.D.H + H⁺.

Recall that four A.T.P molecules are produced via substrate-level phosphorylation (two from glycolysis and two from the Krebs cycle). If the four A.T.P produced via substrate-level phosphorylation are added to the 26 or 28 A.T.P produced via oxidative phosphorylation, a total of either 30 or 32 A.T.P is generated for each molecule of glucose catabolized during cellular respiration. The overall reaction is

Math summary: This equation represents the overall chemical reaction of cellular respiration. It shows glucose and oxygen combining with adenosine diphosphate and inorganic phosphate to produce carbon dioxide, water, and either thirty or thirty two molecules of adenosine triphosphate.

Table 25.1 summarizes the A.T.P yield during cellular respiration. A schematic depiction of the principal reactions of cellular respiration is presented in Figure 25.10.

Table 25.1 summary: The table outlines the cumulative ATP yield from the different stages of cellular respiration per glucose molecule. It shows that while glycolysis and the Krebs cycle provide a small amount of energy through substrate-level phosphorylation, the majority of ATP is generated via oxidative phosphorylation from NADH and FADH2 produced across glycolysis, the formation of acetyl coenzyme A, and the Krebs cycle.

Figure 25.10 summary: This figure is a biological process diagram. It illustrates the stages of cellular respiration, beginning with glycolysis in the cytosol where glucose is converted to pyruvic acid, followed by the transition reaction and the Krebs cycle within the mitochondrial matrix, and concluding with the electron transport chain on the inner mitochondrial membrane. The diagram shows that glucose breakdown leads to the production of energy carriers and waste products, where oxygen is consumed at the final stage to produce water and a significant amount of energy, while carbon dioxide is released as a byproduct during the mitochondrial stages.

Glycolysis, the Krebs cycle, and especially the electron transport chain provide all of the A.T.P for cellular activities. Because the Krebs cycle and electron transport chain are aerobic processes, cells cannot carry on their activities for long if oxygen is lacking.

Glucose Anabolism

Even though most of the glucose in the body is catabolized to generate A.T.P, glucose may take part in or be formed via several anabolic reactions. One is the synthesis of glycogen; another is the synthesis of new glucose molecules from some of the products of protein and lipid breakdown.

Glucose Storage: Glycogenesis If glucose is not needed immediately for A.T.P production, it combines with many other molecules of glucose to form glycogen, a polysaccharide that is the only stored form of carbohydrate in the body. The hormone insulin, from pancreatic beta cells, Figure 25.9 The actions of the three proton pumps and A.T.P synthase in the inner membrane of mitochondria. Each pump is a complex of three or more electron carriers. ① The first proton pump is the N.A.D.H dehydrogenase complex, which contains flavin mononucleotide (F.M.N) and five or more Fe-S centers. N.A.D.H + H⁺ is oxidized to N.A.D⁺, and F.M.N is reduced to F.M.N.H 2, which in turn is oxidized as it passes electrons to the iron-sulfur centers. Q, which is mobile in the membrane, shuttles electrons to the second pump complex. ② The second proton pump is the cytochrome b–c₁ complex, which contains cytochromes and an iron-sulfur center. Electrons are passed successively from Q to cyt b, to Fe-S, to cyt c₁. The mobile shuttle that passes electrons from the second pump complex to the third is cytochrome c (cyt c). ③ The third proton pump is the cytochrome oxidase complex, which contains cytochromes a and a₃ and two copper atoms. Electrons pass from cyt c, to Cu, to cyt a, and finally to cyt a₃. Cyt a₃ passes its electrons to one-half of a molecule of oxygen (O₂), which becomes negatively charged and then picks up two H⁺ from the surrounding medium to form H₂O.

As the three proton pumps pass electrons from one carrier to the next, they also move protons ( H superscript plus ) from the matrix into the space between the inner and outer mitochondrial membranes. As protons flow back into the mitochondrial matrix through the H superscript plus channel in A.T.P synthase, A.T.P is synthesized.

Figure 25.10 Summary of the principal reactions of cellular respiration. E.T.C = electron transport chain and chemiosmosis. stimulates hepatocytes and skeletal muscle fibers to carry out glycogenesis glycogenesis), the synthesis of glycogen (Figure 25.11). The body can store about 500 g (about 1.1 pounds) of glycogen, roughly 75% in skeletal muscle fibers and the rest in liver cells. During glycogenesis, glucose is first phosphorylated to glucose 6-phosphate by hexokinase. Glucose 6-phosphate is

Figure 25.11 summary: This figure is a biochemical pathway diagram. It illustrates the metabolic processes of glycogenesis and glycogenolysis within a hepatocyte, showing the conversion between blood glucose and stored glycogen. The diagram details the enzymatic steps involving hexokinase, phosphatase, and phosphorylase, as well as the intermediate forms of glucose. The figure indicates that insulin stimulates the synthesis of glycogen from glucose, while glucagon and epinephrine stimulate the breakdown of glycogen to release glucose back into the bloodstream.

Chart 25.1 summary: This figure is a biological diagram illustrating the electron transport chain and oxidative phosphorylation within the inner mitochondrial membrane. The diagram depicts the flow of electrons through a series of protein complexes, including NADH dehydrogenase, the cytochrome b-c1 complex, and cytochrome oxidase, which facilitate the movement of protons from the mitochondrial matrix into the intermembrane space. This process creates a proton gradient that drives ATP synthase to convert ADP and inorganic phosphate into ATP. The figure shows that the oxidation of NADH and the reduction of oxygen to water are coupled with the generation of a proton motive force, which ultimately powers the synthesis of energy molecules.

Figure 25.11 Glycogenesis and Glycogenolysis.

converted to glucose 1-phosphate, then to uridine diphosphate glucose, and finally to glycogen.

Glucose Release: Glycogenolysis When body activities require A.T.P, glycogen stored in hepatocytes is broken down into glucose and released into the blood to be transported to cells, where it will be catabolized by the processes of cellular respiration already described. The process of splitting glycogen into its glucose subunits is called glycogenolysis glycogenolysis. (Note: Do not confuse glycogenolysis, the breakdown of glycogen to glucose, with glycolysis, the 10 reactions that convert glucose to pyruvic acid.)

Glycogenolysis is not a simple reversal of the steps of glycogenesis (Figure 25.11). It begins by splitting off glucose molecules from the branched glycogen molecule via phosphorylation to form glucose 1-phosphate. Phosphorylase, the enzyme that catalyzes this reaction, is activated by glucagon from pancreatic alpha cells and epinephrine from the adrenal medullae. Glucose 1-phosphate is then converted to glucose 6-phosphate and finally to glucose, which leaves hepatocytes via glucose transporters (GluT) in the plasma membrane. Phosphorylated glucose molecules cannot ride aboard the GluT transporters, however, and phosphatase, the enzyme that converts glucose 6-phosphate into glucose, is absent in skeletal muscle fibers.

Thus, hepatocytes, which have phosphatase, can release glucose derived from glycogen to the bloodstream, but skeletal muscle fibers cannot. In skeletal muscle fibers, glycogen is broken down into glucose 1-phosphate, which is then catabolized for A.T.P production via glycolysis and the Krebs cycle. However, the lactic acid produced by glycolysis in muscle fibers can be converted to glucose in the liver. In this way, muscle glycogen can be an indirect source of blood glucose.

Carbohydrate Loading

The amount of glycogen stored in the liver and skeletal muscles varies and can be completely exhausted during long-term athletic endeavors. Thus, many marathon runners and other endurance athletes follow a precise exercise and dietary regimen that includes eating large amounts of complex carbohydrates, such as pasta and potatoes, in the three days before an event. This practice, called carbohydrate loading, helps maximize the amount of glycogen available for A.T.P production in muscles. For athletic events lasting more than an hour, carbohydrate loading has been shown to increase an athlete's endurance. The increased endurance is due to increased glycogenolysis, which results in more glucose that can be catabolized for energy.

Formation of Glucose from Proteins and Fats: Gluconeogenesis When your liver runs low on glyco-

Gluconeogenesis When your liver runs low on glycogen, it is time to eat. If you don't, your body starts catabolizing triglycerides (fats) and proteins. Actually, the body normally catabolizes some of its triglycerides and proteins, but large-scale triglyceride and protein catabolism does not happen unless you are starving, eating very few carbohydrates, or suffering from an endocrine disorder.

The glycerol part of triglycerides, lactic acid, and certain amino acids can be converted in the liver to glucose (Figure 25.12). The process by which glucose is formed from these Figure 25.12 Gluconeogenesis, the conversion of noncarbohydrate molecules (amino acids, lactic acid, and glycerol) into glucose. noncarbohydrate sources is called gluconeogenesis glukoneogenesis; neo-= new). An easy way to distinguish this term from glycogenesis or glycogenolysis is to remember that in this case glucose is not converted back from glycogen, but is instead newly formed. About 60% of the amino acids in the body can be used for gluconeogenesis. Lactic acid and amino acids such as alanine, cysteine, glycine, serine, and threonine are converted to pyruvic acid, which then may be synthesized into glucose or enter the Krebs cycle. Glycerol may be converted into glyceraldehyde 3-phosphate, which may form pyruvic acid or be used to synthesize glucose.

Figure 25.12 summary: This figure is a flow chart. It illustrates the metabolic pathways of gluconeogenesis, showing how various non-carbohydrate precursors such as lactic acid, certain amino acids, and glycerol are converted into glucose. The process begins with precursors transforming into pyruvic acid or glyceraldehyde 3-phosphate, which then progress through glucose 6-phosphate to eventually produce glucose. The chart indicates that this synthesis process is stimulated by the hormones cortisol and glucagon. It can be inferred that the body utilizes multiple chemical sources to maintain glucose levels through a series of sequential biochemical conversions.

Gluconeogenesis is stimulated by cortisol, the main glucocorticoid hormone of the adrenal cortex, and by glucagon from the pancreas. In addition, cortisol stimulates the breakdown of proteins into amino acids, thus expanding the pool of amino acids available for gluconeogenesis. Thyroid hormones (thyroxine and triiodothyronine) also mobilize proteins and may mobilize triglycerides from adipose tissue, thereby making glycerol available for gluconeogenesis.

Checkpoint

5. How does glucose move into or out of body cells?

6. What happens during glycolysis?

7. How is acetyl coenzyme A formed?

8. Outline the principal events and outcomes of the Krebs cycle.

9. What happens in the electron transport chain and why is this process called chemiosmosis?

10. Which reactions produce A.T.P during the complete oxidation of a molecule of glucose?

11. Under what circumstances do glycogenesis and glycogenolysis occur?

12. What is gluconeogenesis, and why is it important?

25.4 Lipid Metabolism

Objectives

- Describe the lipoproteins that transport lipids in the blood.

• Discuss the fate, metabolism, and functions of lipids.

Transport of Lipids by Lipoproteins

Most lipids, such as triglycerides, are nonpolar and therefore very hydrophobic molecules. They do not dissolve in water. To be transported in watery blood, such molecules first must be made more water-soluble by combining them with proteins produced by the liver and intestine. The lipid and protein Figure 25.13 A lipoprotein. Shown here is a V.L.D.L. combinations thus formed are lipoproteins lipoproteins, spherical particles with an outer shell of proteins, phospholipids, and cholesterol molecules surrounding an inner core of triglycerides and other lipids (Figure 25.13). The proteins in the outer shell are called apoproteins (apo) apoproteins and are designated by the letters A, B, C, D, and E plus a number. In addition to helping solubilize the lipoprotein in body fluids, each apoprotein has specific functions.

Figure 25.13 summary: This figure is a detailed anatomical diagram of a lipoprotein particle. It illustrates the internal and external composition of the particle, showing a core of nonpolar lipids consisting of triglycerides and cholesterol, surrounded by a shell of amphipathic lipids including phospholipids and cholesterol. Various apolipoproteins, specifically Apo B100, Apo C-2, and Apo E, are embedded in the outer surface. The structure demonstrates how hydrophobic lipids are sequestered in the center while the amphipathic outer layer allows the entire complex to be soluble in the bloodstream, facilitating the transport of cholesterol and other lipids to body cells.

Each of the several types of lipoproteins has different functions, but all are essentially transport vehicles. They provide delivery and pickup services so that lipids can be available when cells need them or removed from circulation when they are not needed. Lipoproteins are categorized and named mainly according to their density, which varies with the ratio of lipids (which have a low density) to proteins (which have a high density). From largest and lightest to smallest and heaviest, the four major classes of lipoproteins are chylomicrons, very-low-density lipoproteins V.L.D.L's, low-density lipoproteins L.D.L's, and high-density lipoproteins H.D.L's.

Chylomicrons (ki-lo-Ml-krons), which form in mucosal epithelial cells of the small intestine, transport dietary (ingested) lipids to adipose tissue for storage. They contain about 1 to 2% proteins, 85% triglycerides, 7% phospholipids, and 6 to 7% cholesterol, plus a small amount of fat-soluble vitamins. Chylomicrons enter lacteals of intestinal villi and are carried by lymph into venous blood and then into the systemic circulation. Their presence gives hla-ma a milky appearance, but they remain in minutes. As chylomicrons tissue, one lipase, an enzyme that removes fatty acids from chylomicron triglycerides. The free fatty acids are then taken up by adipocytes for synthesis and storage as triglycerides and by muscle fibers for A.T.P production. Hepatocytes remove chylomicron remnants from the blood via receptor-mediated endocytosis, in which another chylomicron apoprotein, apo E, is the docking protein.

Very-low-density lipoproteins V.L.D.L's, which form in hepatocytes, contain mainly endogenous (made in the body) lipids. V.L.D.L's contain about 10% proteins, 50% triglycerides, 20% phospholipids, and 20% cholesterol. V.L.D.L's transport triglycerides synthesized in hepatocytes to adipocytes for storage. Like chylomicrons, they lose triglycerides as their apo C.2 activates endothelial lipoprotein lipase, and the resulting fatty acids are taken up by adipocytes for storage and by muscle fibers for A.T.P production. As they deposit some of their triglycerides in adipose cells, V.L.D.L's are converted to L.D.L's.

Low-density lipoproteins L.D.L's contain 25% proteins, 5% triglycerides, 20% phospholipids, and 50% cholesterol. They carry about 75% of the total cholesterol in blood and deliver it to cells throughout the body for use in repair of cell membranes and synthesis of steroid hormones and bile salts. L.D.L's contain a single apoprotein, apo B.100, which is the docking protein that binds to L.D.L receptors on the plasma membrane of body cells so that L.D.L can enter the cell via receptor-mediated endocytosis. Within the cell, the L.D.L is broken down, and the cholesterol is released to serve the cell's needs. Once a cell has sufficient cholesterol for its activities, a negative feedback system inhibits the cell's synthesis of new L.D.L receptors.

When present in excessive numbers, L.D.L's also deposit cholesterol in and around smooth muscle fibers in arteries, forming fatty plaques that increase the risk of coronary artery disease (see Disorders: Homeostatic Imbalances at the end of Chapter 20). For this reason, the cholesterol in L.D.L's, called L.D.L-cholesterol, is known as “bad” cholesterol. Because some people have too few L.D.L receptors, their body cells remove L.D.L from the blood less efficiently; as a result, their plasma L.D.L level is abnormally high, and they are more likely to develop fatty plaques. Eating a high-fat diet increases the production of V.L.D.L's, which elevates the L.D.L level and increases the formation of fatty plaques.

High-density lipoproteins H.D.L's, which contain 40 to 45% proteins, 5 to 10% triglycerides, 30% phospholipids, and 20% cholesterol, remove excess cholesterol from body cells and the blood and transport it to the liver for elimination. Because H.D.L's prevent accumulation of cholesterol in the blood, a high H.D.L level is associated with decreased risk of coronary artery disease. For this reason, H.D.L-cholesterol is known as “good” cholesterol.

Sources and Significance of Blood Cholesterol

There are two sources of cholesterol in the body. Some is present in foods (eggs, dairy products, organ meats, beef, pork, and processed luncheon meats), but most is synthesized by hepatocytes. Fatty foods that don't contain any cholesterol at all can still dramatically increase blood cholesterol level in two ways. First, a high intake of dietary fats stimulates reabsorption of cholesterol-containing bile back into the blood, so less cholesterol is lost in the feces. Second, when saturated fats are broken down in the body, hepatocytes use some of the breakdown products to make cholesterol.

A lipid profile test usually measures total cholesterol (T.C), H.D.L-cholesterol, and triglycerides V.L.D.L's. L.D.L-cholesterol then is calculated by using the following formula: L.D.L-cholesterol = T.C - H.D.L-cholesterol - (triglycerides/5). In the United States, blood cholesterol is usually measured in milligrams per deciliter (milligrams per deciliter); a deciliter is 0.1 liter or 100 mL. For adults, desirable levels of blood cholesterol are total cholesterol under 200 milligrams/dL, L.D.L-cholesterol under 130 milligrams/dL, and H.D.L-cholesterol over 40 milligrams/dL. Normally, triglycerides are in the range of 10 to 190 milligrams/dL.

As total cholesterol level increases, the risk of coronary artery disease begins to rise. When total cholesterol is above 200 milligrams/dL (5.2 millimoles/liter), the risk of a heart attack doubles with every 50 milligrams/dL (1.3 millimoles/liter) increase in total cholesterol. Total cholesterol of 200 to 239 milligrams/dL and L.D.L of 130 to 159 milligrams/dL are borderline-high; total cholesterol above 239 milligrams/dL and L.D.L above 159 milligrams/dL are classified as high blood cholesterol. The ratio of total cholesterol to H.D.L-cholesterol predicts the risk of developing coronary artery disease. For example, a person with a total cholesterol of 180 milligrams/dL and H.D.L of 60 milligrams/dL has a risk ratio of 3. Ratios above 4 are considered undesirable; the higher the ratio, the greater the risk of developing coronary artery disease.

Among the therapies used to reduce blood cholesterol level are exercise, diet, and drugs. Regular physical activity at aerobic and nearly aerobic levels raises H.D.L level. Dietary changes are aimed at reducing the intake of total fat, saturated fats, and cholesterol. Drugs used to treat high blood cholesterol levels include cholestyramine (Questran) and colestipol (Colestid), which promote excretion of bile in the feces; nicotinic acid (Liponicin); and the “statin” drugs—atorvastatin (Lipitor), lovastatin (Mevacor), and simvastatin (Zocor), which block the key enzyme H.M.G-CoA reductase) needed for cholesterol synthesis.

The Fate of Lipids

Lipids, like carbohydrates, may be oxidized to produce A.T.P. If the body has no immediate need to use lipids in this way, they are stored in adipose tissue (fat depots) throughout the body and in the liver. A few lipids are used as structural molecules or to synthesize other essential substances. Some examples include phospholipids, which are constituents of plasma membranes; lipoproteins, which are used to transport cholesterol throughout the body; thromboplastin, which is needed for blood clotting; and myelin sheaths, which speed up nerve impulse conduction.

Two essential fatty acids that the body cannot synthesize are linoleic acid and linolenic acid. Dietary sources include vegetable oils and leafy vegetables.

The various functions of lipids in the body may be reviewed in Table 2.7.

Triglyceride Storage

A major function of adipose tissue is to remove triglycerides from chylomicrons and V.L.D.L's and store them until they are needed for A.T.P production in other parts of the body. Triglycerides stored in adipose tissue constitute 98% of all body energy reserves. They are stored more readily than glycogen, in part because triglycerides are hydrophobic and do not exert osmotic pressure on cell membranes.

Adipose tissue also insulates and protects various parts of the body. Adipocytes in the subcutaneous tissue contain about 50% of the stored triglycerides. Other adipose tissues account for the other half: about 12% around the kidneys, 10 to 15% in the omenta, 15% in genital areas, 5 to 8% between muscles, and 5% behind the eyes, in the sulci of the heart, and attached to the outside of the large intestine.

Triglycerides in adipose tissue are continually broken down and resynthesized. Thus, the triglycerides stored in adipose tissue today are not the same molecules that were present last month because they are continually released from storage, transported in the blood, and redeposited in other adipose tissue cells.

Lipid Catabolism: Lipolysis

In order for muscle, liver, and adipose tissue to oxidize the fatty acids derived from triglycerides to produce A.T.P, the triglycerides must first be split into glycerol and fatty acids, a process called lipolysis lipolysis. Lipolysis is catalyzed by enzymes called lipases. Epinephrine and norepinephrine enhance triglyceride breakdown into fatty acids and glycerol. These hormones are released when sympathetic tone increases, as occurs, for example, during exercise.

Other lipolytic hormones include cortisol, thyroid hormones, and insulinlike growth factors. By contrast, insulin inhibits lipolysis.

The glycerol and fatty acids that result from lipolysis are catabolized via different pathways (Figure 25.14). Glycerol is converted by many cells of the body to glyceraldehyde 3-phosphate, one of the compounds also formed during the catabolism of glucose. If A.T.P supply in a cell is high, glyceraldehyde 3-phosphate is converted into glucose, an example of gluconeogenesis. If A.T.P supply in a cell is low, glyceraldehyde 3-phosphate enters the catabolic pathway to pyruvic acid.

Figure 25.14 summary: This figure is a biochemical pathway diagram. It illustrates the metabolic interconnections between glucose, amino acids, fatty acids, glycerol, triglycerides, and ketone bodies, showing how they converge at acetyl coenzyme A and the Krebs cycle. The diagram indicates that glucose can be converted into pyruvate and then into acetyl coenzyme A, while certain amino acids and fatty acids via beta oxidation also feed into acetyl coenzyme A. Triglycerides are broken down into glycerol and fatty acids through lipolysis, and these components can be synthesized back into triglycerides through lipogenesis. The figure concludes that acetyl coenzyme A can either enter the Krebs cycle for energy production or be converted into ketone bodies through ketogenesis in liver cells, while most other body cells can break down these ketone bodies.

Fatty acids are catabolized differently than glycerol and yield more A.T.P. The first stage in fatty acid catabolism is a series of reactions, collectively called beta oxidation (B {A} -ta), that occurs in the mitochondrial matrix. Enzymes remove two carbon atoms at a time from the long chain of carbon atoms composing a fatty acid and attach the resulting two-carbon fragment to coenzyme A, forming acetyl CoA. Then, acetyl CoA enters the Krebs cycle (Figure 25.14). A 16-carbon fatty acid such as palmitic acid can yield as many as 129 A.T.P's on its complete oxidation via beta oxidation, the Krebs cycle, and the electron transport chain.

Figure 25.14 Pathways of lipid metabolism. Glycerol may be converted to glyceraldehyde 3-phosphate, which can then be converted to glucose or enter the Krebs cycle for oxidation. Fatty acids undergo beta oxidation and enter the Krebs cycle via acetyl coenzyme A. The synthesis of lipids from glucose or amino acids is called lipogenesis.

Glycerol and fatty acids are catabolized in separate pathways.

As part of normal fatty acid catabolism, hepatocytes can take two acetyl CoA molecules at a time and condense them to form acetoacetic acid (as'-ê-tô-a-SÊ-tôk). This reaction liberates the bulky CoA portion, which cannot diffuse out of cells. Some acetoacetic acid is converted into beta-hydroxybutyric acid hydroxibutyric and acetone acetone. The formation of these three substances, collectively known as ketone bodies (KÊ-tôn), is called ketogenesis ketogenesis (Figure 25.14). Because ketone bodies freely diffuse through plasma membranes, they leave hepatocytes and enter the bloodstream.

Other cells take up acetoacetic acid and attach its four carbons to two coenzyme A molecules to form two acetyl CoA molecules, which can then enter the Krebs cycle for oxidation. Heart muscle and the cortex (outer part) of the kidneys use acetoacetic acid in preference to glucose for generating A.T.P. Hepatocytes, which make acetoacetic acid, cannot use it for A.T.P production because they lack the enzyme that transfers acetoacetic acid back to coenzyme A.

Lipid Anabolism: Lipogenesis

Liver cells and adipose cells can synthesize lipids from glucose or amino acids through lipogenesis (Figure 25.14), which is stimulated by insulin. Lipogenesis occurs when individuals consume more calories than are needed to satisfy their A.T.P needs.

Clinical Connection

Ketosis

The level of ketone bodies in the blood normally is very low because other tissues use them for A.T.P production as fast as they are generated from the breakdown of fatty acids in the liver. During periods of excessive beta oxidation, however, the production of ketone bodies exceeds their uptake and use by body cells. This might occur after a meal rich in triglycerides, or during fasting or starvation, because few carbohydrates are available for catabolism.

Excessive beta oxidation may also occur in poorly controlled or untreated diabetes mellitus for two reasons: (1) because adequate glucose cannot get into cells, triglycerides are used for A.T.P production, and (2) because insulin normally inhibits lipolysis, a lack of insulin accelerates the pace of lipolysis. When the concentration of ketone bodies in the blood rises above normal—a condition called ketosis—the ketone bodies, most of which are acids, must be buffered. If too many accumulate, they decrease the concentration of buffers, such as bicarbonate ions, and blood pH falls. Extreme or prolonged ketosis can lead to acidosis (ketoacidosis), an abnormally low blood pH. The decreased blood pH in turn causes depression of the central nervous system, which can result in disorientation, coma, and even death if the condition is not treated. When a diabetic becomes seriously insulin-deficient, one of the telltale signs is the sweet smell on the breath from the ketone body acetone.

Excess dietary carbohydrates, proteins, and fats all have the same fate—they are converted into triglycerides. Certain amino acids can undergo the following reactions: amino acids yields acetyl CoA yields fatty acids yields triglycerides. The use of glucose to form lipids takes place via two pathways: (1) glucose yields glyceraldehyde 3-phosphate yields glycerol and (2) glucose yields glyceraldehyde 3-phosphate yields acetyl CoA yields fatty acids. The resulting glycerol and fatty acids can undergo anabolic reactions to become stored triglycerides, or they can go through a series of anabolic reactions to produce other lipids such as lipoproteins, phospholipids, and cholesterol.

Checkpoint

25.5 Protein Metabolism

Objective

During digestion, proteins are broken down into amino acids. Unlike carbohydrates and triglycerides, which are stored, proteins are not warehoused for future use. Instead, amino acids are either oxidized to produce A.T.P or used to synthesize new proteins for body growth and repair. Excess dietary amino acids are not excreted in the urine or feces but instead are converted into glucose (gluconeogenesis) or triglycerides (lipogenesis).

The Fate of Proteins

The active transport of amino acids into body cells is stimulated by insulin-like growth factors I.G.F's and insulin. Almost immediately after digestion, amino acids are reassembled into proteins. Many proteins function as enzymes; others are involved in transportation (hemoglobin) or serve as antibodies, clotting chemicals (fibrinogen), hormones (insulin), or contractile elements in muscle fibers (actin and myosin). Several proteins serve as structural components of the body (collagen, elastin, and keratin). The various functions of proteins in the body may be reviewed in Table 2.8.

Protein Catabolism

A certain amount of protein catabolism occurs in the body each day, stimulated mainly by cortisol from the suprarenal cortex. Proteins from worn-out cells (such as red blood cells) are broken down into amino acids. Some amino acids are converted into other amino acids, peptide bonds are re-formed, and new proteins are synthesized as part of the recycling process.

Hepatocytes convert some amino acids to fatty acids, ketone bodies, or glucose. Cells throughout the body oxidize a small amount of amino acids to generate A.T.P via the Krebs cycle and the electron transport chain. However, before amino acids can be oxidized, they must first be converted to molecules that are part of the Krebs cycle or can enter the Krebs cycle, such as acetyl CoA (Figure 25.15). Before amino acids can enter the Krebs cycle, their amino group N.H.2 must first be removed—a process called deamination (dé-am'-i-NÃ-shun). Deamination occurs in hepatocytes and produces ammonia N.H.3. The liver cells then convert the highly toxic ammonia to urea, a relatively harmless substance that is excreted in the urine. The conversion of amino acids into glucose (gluconeogenesis) may be reviewed in Figure 25.12; the conversion of amino acids into fatty acids (lipogenesis) or ketone bodies (ketogenesis) is shown in Figure 25.14.

Figure 25.15 summary: This figure is a biochemical pathway diagram. It illustrates the various points of entry for different amino acids into the Krebs cycle, showing how they are converted into metabolic intermediates such as pyruvic acid, acetyl CoA, oxaloacetic acid, alpha-ketoglutarate, succinyl CoA, and fumaric acid. The diagram demonstrates that amino acids are categorized based on which specific molecule they transform into before entering the cycle. It can be inferred that the Krebs cycle serves as a central hub for the catabolism of diverse amino acids, allowing the body to utilize protein-derived carbon skeletons for energy production depending on the specific chemical structure of the amino acid.

Protein Anabolism

Protein anabolism, the formation of peptide bonds between amino acids to produce new proteins, is carried out on the ribosomes of almost every cell in the body, directed by the cells' D.N.A and R.N.A (see Figure 3.29). Insulin-like growth factors, thyroid hormones (T₃ and T₄), insulin, estrogens, and testosterone all stimulate protein synthesis. Because proteins are a main component of most cell structures, adequate dietary protein is especially essential during the growth years, during pregnancy, and when tissue has been damaged by disease or injury. Once dietary intake of protein is adequate, eating more protein will not increase bone or muscle mass; only a regular program of forceful, weight-bearing muscular activity accomplishes that goal.

Of the 20 amino acids in the human body, 10 are essential amino acids: They must be present in the diet because they cannot be synthesized in the body in adequate amounts. It is essential to include them in your diet. Humans are unable to synthesize eight amino acids (isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine) and synthesize two others (arginine and histidine) in inadequate amounts, especially in childhood. A complete protein contains sufficient amounts of all essential amino acids.

Beef, fish, poultry, eggs, and milk are examples of foods that contain complete proteins. An incomplete protein does not contain all essential Figure 25.15 Points at which amino acids (yellow boxes) enter the Krebs cycle for oxidation.

Before amino acids can be catabolized, they must first be converted to various substances that can enter the Krebs cycle.

Clinical Connection

Phenylketonuria

Phenylketonuria (P.K.U) phenylketonurea is a genetic error of protein metabolism characterized by elevated blood levels of the amino acid phenylalanine. Most children with phenylketonuria have a mutation in the gene that codes for the enzyme phenylalanine hydroxylase, the enzyme needed to convert phenylalanine into the amino acid tyrosine, which can enter the Krebs cycle (Figure 25.15). Because the enzyme is deficient, phenylalanine cannot be metabolized, and what is not used in protein synthesis builds up in the blood. If untreated, the disorder causes vomiting, rashes, seizures, growth deficiency, and severe mental retardation. Newborns are screened for P.K.U, and mental retardation can be prevented by restricting the affected child to a diet that supplies only the amount of phenylalanine needed for growth, although learning disabilities may still ensue. Because the artificial sweetener aspartame (NutraSweet) contains phenylalanine, its consumption must be restricted in children with P.K.U. amino acids. Examples of incomplete proteins are leafy green vegetables, legumes (beans and peas), and grains. Nonessential amino acids can be synthesized by body cells. They are formed by transamination (trans'-am-i-N Delta -shun), the transfer of an amino group from an amino acid to pyruvic acid or to an acid in the Krebs cycle. Once the appropriate essential and nonessential amino acids are present in cells, protein synthesis occurs rapidly.

Checkpoint

19. What is deamination and why does it occur?

20. What are the possible fates of the amino acids from protein catabolism?

21. How are essential and nonessential amino acids different?

25.6 Key Molecules at Metabolic Crossroads

Objective

- Describe the reactions of key molecules and the products formed during metabolism.

Although there are thousands of different chemicals in cells, three molecules—glucose 6-phosphate, pyruvic acid, and acetyl coenzyme A—play pivotal roles in metabolism (Figure 25.16). These molecules stand at “metabolic crossroads”; as you will learn shortly, the reactions that occur (or do not occur) depend on the nutritional or activity status of the individual. Reactions

Figure 25.16 summary: This figure is a metabolic pathway diagram. It illustrates the interconnected biochemical processes of glucose metabolism, including glycolysis in the cytosol, the Krebs cycle and the electron transport chain in the mitochondria, and the integration of amino acids, glycogen, and lipids into these pathways. The diagram shows how glucose is converted to glucose 6-phosphate and then to pyruvic acid, which can either enter anaerobic reactions to produce lactic acid or aerobic reactions to form acetyl coenzyme A. Acetyl coenzyme A serves as the primary entry point into the Krebs cycle, which subsequently provides electrons for the electron transport chain to generate ATP and water. The figure demonstrates that the metabolic network is highly flexible, allowing for the interconversion of carbohydrates, proteins, and fats depending on the energy needs and oxygen availability of the cell.

Figure 25.16 Summary of the Roles of the Key Molecules in Metabolic Pathways. Double-

Figure 25.10. The notes of the key molecules in metabolic pathways. Double-headed arrows indicate that reactions between two molecules may proceed in either direction, if the appropriate enzymes are present and the conditions are favorable; single-headed arrows signify the presence of an irreversible step.

Three molecules—glucose 6-phosphate, pyruvic acid, and acetyl coenzyme A—stand at “metabolic crossroads.” They can undergo different reactions depending on your nutritional or activity status. ① through ⑦ in Figure 25.16 occur in the cytosol, reactions ⑧ and ⑨ occur inside mitochondria, and reactions indicated by ⑩ occur on smooth endoplasmic reticulum.

The Role of Glucose 6-Phosphate

Shortly after glucose enters a body cell, a kinase converts it to glucose 6-phosphate. Four possible fates await glucose 6-phosphate (see Figure 25.16): ① Synthesis of glycogen. When glucose is abundant in the bloodstream, as it is just after a meal, a large amount of glucose 6-phosphate is used to synthesize glycogen, the storage form of carbohydrate in animals. Subsequent breakdown of glycogen into glucose 6-phosphate occurs through a slightly different series of reactions. Synthesis and breakdown of glycogen occur mainly in skeletal muscle fibers and hepatocytes. ② Release of glucose into the bloodstream. If the enzyme glucose 6-phosphatase is present and active, glucose 6-phosphate can be dephosphorylated to glucose. Once glucose is released from the phosphate group, it can leave the cell and enter the bloodstream. Hepatocytes are the main cells that can provide glucose to the bloodstream in this way.

3 Synthesis of nucleic acids. Glucose 6-phosphate is the precursor used by cells throughout the body to make ribose 5-phosphate, a 5-carbon sugar that is needed for synthesis of R.N.A (ribonucleic acid) and D.N.A (deoxyribonucleic acid). The same sequence of reactions also produces N.A.D.P.H. This molecule is a hydrogen and electron donor in certain reduction reactions, such as synthesis of fatty acids and steroid hormones. ④ Glycolysis. Some A.T.P is produced anaerobically via glycolysis, in which glucose 6-phosphate is converted to pyruvic acid, another key molecule in metabolism. Most body cells carry out glycolysis.

The Role of Pyruvic Acid

Each 6-carbon molecule of glucose that undergoes glycolysis yields two 3-carbon molecules of pyruvic acid pyruvic. This molecule, like glucose 6-phosphate, stands at a metabolic crossroads: Given enough oxygen, the aerobic (oxygen-consuming) reactions of cellular respiration can proceed; if oxygen is in short supply, anaerobic reactions can occur (Figure 25.16):

5 Production of lactic acid. When oxygen is in short supply in a tissue, as in actively contracting skeletal or cardiac muscle, some pyruvic acid is changed to lactic acid. The lactic acid then diffuses into the bloodstream and is taken up by hepatocytes, which eventually convert it back to pyruvic acid.

6 Production of alanine. Carbohydrate and protein metabolism are linked by pyruvic acid. Through transamination, an amino group ( N.H 2 ) can either be added to pyruvic acid (a carbohydrate) to produce the amino acid alanine, or be removed from alanine to generate pyruvic acid.

7 Gluconeogenesis. Pyruvic acid and certain amino acids also can be converted to oxaloacetic acid, one of the Krebs cycle intermediates, which in turn can be used to form glucose 6-phosphate. This sequence of gluconeogenesis reactions bypasses certain one-way reactions of glycolysis.

The Role of Acetyl Coenzyme A

8 When the A.T.P level in a cell is low but oxygen is plentiful, most pyruvic acid streams toward A.T.P-producing reactions—the Krebs cycle and electron transport chain—via conversion to acetyl coenzyme A.

9 Entry into the Krebs cycle. Acetyl CoA is the vehicle for 2-carbon acetyl groups to enter the Krebs cycle. Oxidative Krebs cycle reactions convert acetyl CoA to C-O₂ and produce reduced coenzymes (N.A.D.H and F.A.D.H₂) that transfer electrons into the electron transport chain. Oxidative reactions in the electron transport chain in turn generate A.T.P. Most fuel molecules that will be oxidized to generate A.T.P—glucose, fatty acids, and ketone bodies—are first converted to acetyl CoA.

10 Synthesis of lipids. Acetyl CoA also can be used for synthesis of certain lipids, including fatty acids, ketone bodies, and cholesterol. Because pyruvic acid can be converted to acetyl CoA, carbohydrates can be turned into triglycerides; this metabolic pathway stores some excess carbohydrate calories as fat. Mammals, including humans, cannot reconvert acetyl CoA to pyruvic acid, however, so fatty acids cannot be used to generate glucose or other carbohydrate molecules.

Table 25.2 is a summary of carbohydrate, lipid, and protein metabolism.

Table 25.2 summary: This table outlines the metabolic processes for carbohydrates, lipids, and proteins. For carbohydrates, it details the stages of glucose catabolism, noting that the electron transport chain generates the most ATP, while also describing glucose anabolism and storage. Lipid metabolism covers the breakdown of triglycerides into glycerol and fatty acids for energy or ketone production, as well as their synthesis for storage. Protein metabolism describes the oxidation of amino acids via the Krebs cycle following deamination, the excretion of urea, and the DNA-directed synthesis of new proteins.

Checkpoint

22. What are the possible fates of glucose 6-phosphate, pyruvic acid, and acetyl coenzyme A in a cell?

25.7 Metabolic Adaptations

Objective

• Compare metabolism during the absorptive and postabsorptive states.

Regulation of metabolic reactions depends both on the chemical environment within body cells, such as the levels of A.T.P and oxygen, and on signals from the nervous and endocrine systems. Some aspects of metabolism depend on how much time has passed since the last meal. During the absorptive state, ingested nutrients are entering the bloodstream, and glucose is readily available for A.T.P production. During the postabsorptive state, absorption of nutrients from the digestive canal is complete, and energy needs must be met by fuels already in the body. A typical meal requires about 4 hours for complete absorption; given three meals a day, the absorptive state exists for about 12 hours each day. Assuming no between-meal snacks, the other 12 hours—typically late morning, late afternoon, and most of the night—are spent in the postabsorptive state.

Because the nervous system and red blood cells continue to depend on glucose for A.T.P production during the postabsorptive state, maintaining a steady blood glucose level is critical during this period. Hormones are the major regulators of metabolism in each state. The effects of insulin dominate in the absorptive state; several other hormones regulate metabolism in the postabsorptive state. During fasting and starvation, many body cells turn to ketone bodies for A.T.P production, as noted in the Clinical Connection on Ketosis in Section 25.4.

Metabolism During the Absorptive State

Soon after a meal, nutrients start to enter the blood. Recall that ingested food reaches the bloodstream mainly as glucose, amino acids, and triglycerides (in chylomicrons).

Absorptive State Reactions During the absorptive state, some of the absorbed nutrients are catabolized for the body's energy needs or are used to synthesize proteins. The following reactions of the absorptive state reflect this function (Figure 25.17):

Figure 25.17 summary: This figure is a metabolic pathway diagram. It illustrates the transport and biochemical conversion of nutrients such as glucose, amino acids, and triglycerides between the digestive canal, blood, liver hepatocytes, skeletal muscle, and adipose tissue. The diagram tracks the flow of these molecules and their transformation into energy or storage forms like glycogen and fats. The content indicates that the liver acts as a central hub for processing nutrients absorbed from the digestive system, distributing them to other tissues or storing them for later use. It can be inferred that the body maintains energy homeostasis by shifting between the utilization of glucose for immediate energy and the storage of excess nutrients as glycogen in muscles and liver or as triglycerides in adipose tissue.

- ① Catabolism of glucose. Most cells of the body produce the majority of their A.T.P by catabolizing glucose via cellular respiration. Hence glucose is the body's main energy source during the absorptive state. About 50% of the glucose absorbed from a typical meal is catabolized by cells throughout the body to produce A.T.P.

- ② Catabolism of amino acids. Some amino acids enter hepatocytes (liver cells), where they are deaminated to keto acids. The keto acids in turn can either enter the Krebs cycle for A.T.P production or be used to synthesize glucose or fatty acids.

- ③ Protein synthesis. Many amino acids enter body cells, such as muscle fibers and hepatocytes, for synthesis of proteins.

- ④ Catabolism of few dietary lipids. During the absorptive state, only a small portion of dietary lipids are catabolized for energy; most dietary lipids are stored in adipose tissue.

Another key event of the absorptive state is that absorbed nutrients in excess of the body's energy needs are converted into nutrient stores—namely glycogen and fat. This Figure 25.17 Principal metabolic pathways during the absorptive state. function is reflected by the following absorptive state reactions (Figure 25.17):

5 Glycogenesis. Some of the glucose that may be in excess of the body's needs in taken up by the liver and skeletal muscle and then converted into glycogen (glycogenesis).

Lipogenesis. The liver can also convert excess glucose or amino acids to fatty acids for use in the synthesis of triglycerides (lipogenesis). Adipocytes also take up glucose not picked up by the liver and convert it into triglycerides for storage. Overall, about 40% of the glucose absorbed from a meal is converted to triglycerides, and about 10% is stored as glycogen in skeletal muscles and the liver.

7 Transport of triglycerides from liver to adipose tissue. Some fatty acids and triglycerides synthesized in the liver remain there, but hepatocytes package most into very low-density lipoproteins V.L.D.L's, which carry lipids to adipose tissue for storage.

Regulation of Metabolism During the Absorp-

tive State Soon after a meal, glucose-dependent insulinotropic peptide G.I.P, plus the rising blood levels of glucose and certain amino acids, stimulates pancreatic beta cells to release the hormone insulin. In general, insulin increases the activity of enzymes needed for anabolism and the synthesis of storage molecules; at the same time, it decreases the activity of enzymes needed for catabolic or breakdown reactions. Insulin promotes the entry of glucose and amino acids into cells of many tissues, and it stimulates the conversion of glucose to glycogen (glycogenesis) in both liver and muscle cells. In liver and adipose tissue, insulin enhances the synthesis of triglycerides (lipogenesis), and in cells throughout the body, insulin stimulates protein synthesis. (See Section 18.10 to review the effects of insulin.) Insulin-like growth factors and the thyroid hormones ( T 3 and T 4 ) also stimulate protein synthesis.

Before glucose can be used by body cells, it must first pass through the plasma membrane and enter the cytosol.

Glucose entry into most body cells occurs via glucose transporter (glut) molecules, a family of transporters that bring glucose into cells via facilitated diffusion. A high level of insulin increases the insertion of one type of glut, called glut4, into the plasma membranes of most body cells (especially muscle fibers and adipocytes), increasing the rate of facilitated diffusion of glucose into cells. In neurons and hepatocytes, however, other types of glut's are always present in the plasma membrane, so glucose entry is always “turned on.” Upon entering a cell, glucose becomes phosphorylated.

Because glut cannot transport phosphorylated glucose, this reaction traps glucose within the cell. Table 25.3 summarizes the hormonal regulation of metabolism in the absorptive state.

Table 25.3 summary: This table outlines the metabolic processes occurring during the absorptive state, highlighting that insulin is the primary hormone driving the uptake of glucose and amino acids, as well as the synthesis of glycogen, proteins, and triglycerides across various body tissues. While insulin is the dominant regulator for most of these anabolic processes, protein synthesis is additionally stimulated by thyroid hormones and insulinlike growth factors.

Metabolism During the Postabsorptive State

About 4 hours after the last meal, absorption of nutrients from the small intestine is complete, and the blood glucose level starts to fall because glucose continues to leave the bloodstream and enter body cells while none is being absorbed from the digestive canal. Thus, the main metabolic challenge during the postabsorptive state is to maintain the normal blood glucose level of 70 to 110 milligrams/100 mL (3.9 to 6.1 millimoles/liter). Homeostasis of blood glucose concentration is especially important for the nervous system and for red blood cells for the following reasons:

• The dominant fuel molecule for A.T.P production in the nervous system is glucose because fatty acids are unable to pass the blood-brain barrier.

- Red blood cells derive all of their A.T.P from glycolysis of glucose because they have no mitochondria, so the Krebs cycle and the electron transport chain are not available to them.

Postabsorptive State Reactions A key feature of the postabsorptive state is that the blood glucose concentration is maintained at a normal level due to the breakdown of the body's nutrient stores (glycogen and fat) and the formation of new glucose from noncarbohydrate sources (gluconeogenesis). The reactions of the postabsorptive state that produce glucose are as follows (Figure 25.18):

① Glycogenolysis in the liver. During the postabsorptive state, a major source of blood glucose is liver glycogenolysis, which can provide about a 4-hour supply of glucose. Once glycogenolysis occurs in the liver, the glucose is released into the blood.

② Glycogenolysis in muscle. Glycogenolysis can also occur in skeletal muscle. However, in skeletal muscle, the glucose that is formed from glycogenolysis is catabolized to provide A.T.P for muscle contraction: Glycogen is broken down to glucose 6-phosphate, which undergoes glycolysis. If anaerobic conditions exist in the skeletal muscle, the pyruvic acid is converted to lactic acid, which is released into the blood. The liver takes up the lactic acid, converts it back to glucose, and then releases glucose into the blood.

Figure 25.18 summary: This figure is a biological pathway diagram. It illustrates the metabolic interactions and the transport of nutrients between various organs and tissues, including the liver, skeletal muscle, adipose tissue, heart, nervous tissue, and other peripheral tissues, specifically during states of fasting or starvation. The diagram shows how the liver acts as a central hub, converting amino acids, lactic acid, and glycerol into glucose to maintain blood glucose levels, while also producing ketone bodies from fatty acids. Inferences from the figure indicate that during the postabsorptive state, blood glucose is elevated through glycogenolysis of liver glycogen and gluconeogenesis utilizing precursors like lactic acid and amino acids. Additionally, the heart and other tissues shift toward using fatty acids and ketone bodies for energy production to spare glucose for the nervous tissue.

3 Lipolysis. In adipose tissue, triglycerides are broken down into fatty acids and glycerol, which are released into the blood. The glycerol is taken up by the liver and then converted into glucose, which in turn is released into the bloodstream.

④ Protein catabolism. Modest breakdown of proteins in skeletal muscle and other tissues releases amino acids, which then can be converted to glucose by the liver. The glucose in turn is released into the bloodstream.

5 Gluconeogenesis. During the postabsorptive state, new glucose is formed from noncarbohydrate sources. Examples of gluconeogenesis include the formation of glucose from lactic acid, glycerol, or an amino acid.

Another hallmark feature of the postabsorptive state is that glucose sparing occurs. Glucose sparing means that most body cells switch to other fuels besides glucose as their main source of energy, leaving more glucose in the blood for the brain and red blood cells. The following reactions produce A.T.P without using glucose (Figure 25.18):

⑥ Catabolism of fatty acids. The fatty acids released by lipolysis of triglycerides cannot be used for glucose production because acetyl CoA cannot be readily converted to pyruvic acid. But most cells can catabolize the fatty acids directly, feed them into the Krebs cycle as acetyl CoA, and produce A.T.P through the electron transport chain.

7 Catabolism of lactic acid. Cardiac muscle can produce A.T.P aerobically from lactic acid.

Catabolism of amino acids. In hepatocytes, amino acids may be catabolized directly to produce A.T.P.

Catabolism of ketone bodies. Hepatocytes also convert fatty acids to ketone bodies (acetoacetic acid, beta-hydroxybutyric acid, and acetone), which can be used by the heart, kidneys, and other tissues for A.T.P production.

Figure 25.18 Principal metabolic pathways during the postabsorptive state.

The principal function of postabsorptive state reactions is to maintain a normal blood glucose level.

Regulation of Metabolism During the Post-absorptive State Both hormones and the sympathetic division of the autonomic nervous system (A.N.S) regulate metabolism during the postabsorptive state. The hormones that regulate postabsorptive state metabolism sometimes are called anti-insulin hormones because they counter the effects of insulin during the absorptive state. As blood glucose level declines, the secretion of insulin falls and the release of anti-insulin hormones rises.

When blood glucose concentration starts to drop, the pancreatic alpha cells release the hormone glucagon. The primary target tissue of glucagon is the liver; the major effect is increased release of glucose into the bloodstream due to gluconeogenesis and glycogenolysis.

Low blood glucose also activates the sympathetic branch of the A.N.S. Glucose-sensitive neurons in the hypothalamus detect low blood glucose and increase sympathetic output. As a result, sympathetic nerve endings release the neurotransmitter norepinephrine, and the suprarenal medullae release two catecholamine hormones—epinephrine and norepinephrine—into the bloodstream. Like glucagon, epinephrine stimulates glycogen breakdown. Epinephrine and norepinephrine are both potent stimulators of lipolysis. These actions of the catecholamines help to increase glucose and free fatty acid levels in the blood. As a result, muscle uses more fatty acids for A.T.P production, and more glucose is available to the nervous system.

Stressful situations such as low blood glucose, hot or cold temperatures, fear, or trauma ultimately cause the release of the hormone cortisol from the suprarenal gland. Cortisol in turn promotes gluconeogenesis, lipolysis, and protein catabolism.

Table 25.4 summarizes the hormonal regulation of metabolism in the postabsorptive state.

Table 25.4 summary: This table outlines the hormonal regulation of metabolic processes during the postabsorptive state, detailing the specific locations and primary stimulating hormones for catabolic activities. It highlights that glycogenolysis and gluconeogenesis occur primarily in the liver to maintain glucose levels, while lipolysis and protein breakdown occur in adipose tissue and muscle fibers respectively, driven by a variety of hormones including glucagon, epinephrine, and cortisol.

Metabolism During Fasting and Starvation

The term fasting means going without food for many hours or a few days; starvation implies weeks or months of food deprivation or inadequate food intake. People can survive without food for 2 months or more if they drink enough water to prevent dehydration. Although glycogen stores are depleted within a few hours of beginning a fast, catabolism of stored triglycerides and structural proteins can provide energy for several weeks. The amount of adipose tissue the body contains determines the life span possible without food.

During fasting and starvation, nervous tissue and R.B.C's continue to use glucose for A.T.P production. There is a ready supply of amino acids for gluconeogenesis because lowered insulin and increased cortisol levels slow the pace of protein synthesis and promote protein catabolism. Most cells in the body, especially skeletal muscle fibers (because of their high protein content), can spare a fair amount of protein before their performance is adversely affected. During the first few days of fasting, protein catabolism outpaces protein synthesis by about 75 grams daily as some of the "old" amino acids are being deaminated and used for gluconeogenesis and "new" (dietary) amino acids are lacking.

By the second day of a fast, blood glucose level has stabilized at about 65 milligrams/100 mL (3.6 millimoles/liter); at the same time the level of fatty acids in plasma has risen fourfold. Lipolysis of triglycerides in adipose tissue releases glycerol, which is used for gluconeogenesis, and fatty acids. The fatty acids diffuse into muscle fibers and other body cells, where they are used to produce acetyl CoA, which enters the Krebs cycle. A.T.P then is synthesized as oxidation proceeds via the Krebs cycle and the electron transport chain.

The most dramatic metabolic change that occurs with fasting and starvation is the increase in the formation of ketone bodies by hepatocytes. During fasting, only small amounts of glucose undergo glycolysis to pyruvic acid, which in turn can be converted to oxaloacetic acid. Acetyl CoA enters the Krebs cycle by combining with oxaloacetic acid (see Figure 25.16); when oxaloacetic acid is scarce due to fasting, only some of the available acetyl CoA can enter the Krebs cycle. Surplus acetyl CoA is used for ketogenesis, mainly in hepatocytes. Ketone body production thus increases as catabolism of fatty acids rises. Lipid-soluble ketone bodies can diffuse through plasma membranes and across the blood-brain barrier and be used as an alternative fuel for A.T.P production, especially by cardiac and skeletal muscle fibers and neurons. Normally, only a trace of ketone bodies (0.01 millimoles/liter) are present in the blood, so they are a negligible fuel source. After 2 days of fasting, however, the level of ketones is 100 to 300 times higher and supplies roughly a third of the brain's fuel for A.T.P production. By 40 days of starvation, ketones provide up to two-thirds of the brain's energy needs. The presence of ketones actually reduces the use of glucose for A.T.P production, which in turn decreases the demand for gluconeogenesis and slows the catabolism of muscle proteins later in starvation to about 20 grams daily.

Checkpoint

23. What are the roles of insulin, glucagon, epinephrine, insulinlike growth factors, thyroxine, cortisol, estrogen, and testosterone in regulation of metabolism?

24. Why is ketogenesis more significant during fasting or starvation than during normal absorptive and postabsorptive states?

25.8 Energy Balance

Objectives

• Explain what is meant by the term energy balance.

• Discuss the various factors that affect metabolic rate.

• Describe the role of the hypothalamus in the regulation of food intake.

Energy balance refers to the precise matching of energy intake (in food) to energy expenditure over time. When the energy content of food balances the energy used by all cells of the body, body weight remains constant (unless there is a gain or loss of water). In many people, weight stability persists despite large day-to-day variations in activity and food intake. In the more affluent nations, however, a large fraction of the population is overweight. Easy access to tasty, high-calorie foods and a “couch-potato” lifestyle both promote weight gain. Being overweight increases the risk of dying from a variety of cardiovascular and metabolic disorders, including hypertension, varicose veins, diabetes mellitus, arthritis, and certain cancers.

Food Calories

As you learned in Chapter 4, when catabolic reactions occur, energy is released. About 40% of this energy is used to perform biological work, such as active transport and muscle contraction. The remaining 60% is converted to heat, some of which helps maintain normal body temperature. Excess heat is lost to the environment. When the body catabolizes the organic compounds in food, the heat energy released can be measured in units called calories. A calorie (cal) is defined as the amount of energy in the form of heat required to raise the temperature of 1 gram of water 1 degree Celsius. Because the calorie is a relatively small unit, the kilocalorie (kilocalories) or Calorie (Cal) (always spelled with an uppercase C) is often used to express the energy content of foods. A kilocalorie equals 1000 calories. Thus, when we say that a particular food item contains 500 Calories, we are actually referring to kilocalories.

Essentially all of the kilocalories in our food come from the catabolism of carbohydrates, proteins, and fats. The catabolism of carbohydrates or proteins yields about the same amount of energy—about 4 kilocalories/g. The catabolism of fat yields much more energy—about 9 kilocalories/g. Some foods or beverages may contain alcohol, and the catabolism of alcohol also yields energy—about 7 kilocalories/g. The energy content of carbohydrates, proteins, fats, and alcohol is summarized in Table 25.5.

Table 25.5 summary: The table compares the energy density of different nutrients and alcohol, showing that fats provide the highest energy content per gram, followed by alcohol, while carbohydrates and proteins provide the lowest and equivalent amounts of energy.

The number of kilocalories from a component in a particular food can be calculated by multiplying the number of grams of that component by its energy content. For example, suppose that one slice of pizza contains 27 g of carbohydrate, 14 g of fat, and 12 g of protein. To calculate the number of kilocalories from carbohydrate in this slice of pizza, multiply the number of grams of carbohydrate in the pizza by the energy content of carbohydrates: 27 g carbohydrate × 4 kilocalories/g = 108 kilocalories. To calculate the number of kilocalories from fat in the slice of pizza, multiply the number of grams of fat in the pizza by the energy content of fat: 14 g fat × 9 kilocalories/g = 126 kilocalories. To calculate the number of kilocalories from protein in the slice of pizza, multiply the number of grams of protein in the pizza by the energy content of protein: 12 g protein × 4 kilocalories/g = 48 kilocalories. Finally, to calculate the total kilocalories in the slice of pizza, add together all of the kilocalories from carbohydrate, fat, and protein: 108 kilocalories + 126 kilocalories + 48 kilocalories = 282 kilocalories.

Table 25.6 lists the caloric content of several familiar foods. The higher the caloric content of a particular food, the greater the amount of energy released as it is catabolized. For example, the energy content of one medium apple is 80 kilocalories; this means that 80 kilocalories is the amount of energy released as the apple is catabolized. The energy content of a slice of chocolate cake is 247 kilocalories; this means that 247 kilocalories is the amount of energy released as the chocolate cake is catabolized. Suppose that you eat the apple or the chocolate cake. Based on the caloric content of these foods, your body will have to work harder (via exercise, for example) to release more energy in order to catabolize the chocolate cake compared with the apple.

Table 25.6 summary: This table compares the nutritional profiles of various foods, showing that processed fast foods and desserts generally contain significantly higher energy, carbohydrates, and fats compared to whole foods like fruits, vegetables, and lean proteins. While lean meats are primary sources of protein with minimal carbohydrates, fast food items and sweets exhibit the highest overall caloric density across multiple macronutrients.

Beverages can also be a source of calories. For example, a cola soft drink (12 ounces) contains 40 g of carbohydrate, 0 g of protein, and 0 g of fat, so the energy content of this soda is 160 kilocalories (40 g carbohydrate × 4 kilocalories/g). A typical serving of vodka (1.5 ounces) contains 0 g of carbohydrate, 0 g of protein, 0 g of fat, and 14 g of alcohol, so the energy content of this drink is 98 calories (14 g × 7 kilocalories/g). If juice, soda, or cocktail mix is added to the vodka, these solutions usually contain carbohydrates that contribute additional calories. Table 25.7 lists the caloric content of several beverages.

Table 25.7 summary: This table compares the nutritional content of various beverages, showing that soft drinks have the highest energy and carbohydrate levels. Milk provides a balanced mix of fats and proteins, while fruit juices are primarily composed of carbohydrates. Alcoholic beverages generally contain lower energy levels than soft drinks and milk, with distilled spirits consisting almost entirely of alcohol and minimal other nutrients.

Metabolic Rate

The overall rate at which metabolic reactions use energy is termed the metabolic rate. As you have already learned, some of the energy is used to produce A.T.P, and some is released as heat. Thus, the higher the metabolic rate, the higher the rate of heat production.

Several factors affect the metabolic rate:

• Hormones. Thyroid hormones (thyroxine and triiodothyronine) are the main regulators of basal metabolic rate (B.M.R), the metabolic rate under basal conditions (described shortly). B.M.R increases as the blood levels of thyroid hormones rise. The response to changing levels of thyroid hormones is slow, however, taking several days to appear. Thyroid hormones increase B.M.R in part by stimulating cellular respiration.

As cells use more oxygen to produce A.T.P, more heat is given off, and body temperature rises. This effect of thyroid hormones on B.M.R is called the calorigenic effect. Other hormones have minor effects on B.M.R. Testosterone, insulin, and growth hormone can increase the metabolic rate by 5 to 15%.

• Exercise. During strenuous exercise, the metabolic rate may increase to as much as 15 times the basal rate. In well-trained athletes, the rate may increase up to 20 times.

• Nervous system. During exercise or in a stressful situation, the sympathetic division of the autonomic nervous system is stimulated. Its postganglionic neurons release norepinephrine N.E, and it also stimulates release of the hormones epinephrine and norepinephrine by the suprarenal medulla. Both epinephrine and norepinephrine increase the metabolic rate of body cells.

• Body temperature. The higher the body temperature, the higher the metabolic rate. Each 1 superscript circle C rise in core temperature increases the rate of biochemical reactions by about 10%. As a result, metabolic rate may be increased substantially during a fever.

• Ingestion of food. The ingestion of food raises the metabolic rate 10 to 20% due to the energy “costs” of digesting, absorbing, and storing nutrients. This effect, food-induced thermogenesis, is greatest after eating a high-protein meal and is less after eating carbohydrates and lipids.

• Age. The metabolic rate of a child, in relation to its size, is about double that of an elderly person due to the high rates of reactions related to growth.

• Other factors. Other factors that affect metabolic rate include gender (lower in females, except during pregnancy and lactation), climate (lower in tropical regions), sleep (lower), and malnutrition (lower).

Basal Metabolic Rate

Because many factors affect metabolic rate, it is measured under standard conditions, with the body in a quiet, resting, and fasting condition called the basal state. The measurement obtained under these conditions is the basal metabolic rate (B.M.R). The most common way to determine B.M.R is by measuring the amount of oxygen used per kilocalorie of food metabolized. When the body uses 1 liter of oxygen to catabolize a typical dietary mixture of triglycerides, carbohydrates, and proteins, about 4.8 kilocalories of energy is released. B.M.R is 1200 to 1800 kilocalories/day in adults, or about 24 kilocalories/kg of body mass in adult males and 22 kilocalories/kg in adult females. The added calories needed to support daily activities, such as digestion and walking, range from 500 kilocalories for a small, relatively sedentary person to over 3000 kilocalories for a person in training for Olympic-level competitions or mountain climbing.

Total Metabolic Rate

The total metabolic rate (T.M.R) is the total energy expenditure by the body per unit of time. Three components contribute to the T.M.R:

1. Basal metabolic rate. The basal metabolic rate accounts for about 60% of the T.M.R.

2. Physical activity. Physical activity typically adds 30 to 35% but can be lower in sedentary people. The energy expenditure is partly from voluntary exercise, such as walking, and partly from nonexercise activity thermogenesis (neat), the energy costs for maintaining muscle tone, posture while sitting or standing, and involuntary fidgeting movements. Table 25.8 lists various activities and the calories that they burn per hour.

Table 25.8 summary: The data compares the hourly energy expenditure across a variety of activities, showing that vigorous physical exercises like swimming and running result in the highest calorie release, while sedentary tasks such as texting and talking on the phone result in the lowest.

3. Food-induced thermogenesis. Food-induced thermogenesis—the heat produced while food is being digested, absorbed, and stored—represents 5 to 10% of the T.M.R.

Adipose Tissue and Stored Chemical Energy

The major site of stored chemical energy in the body is adipose tissue. When energy use exceeds energy input, triglycerides in adipose tissue are catabolized to provide the extra energy, and when energy input exceeds energy expenditure, triglycerides are stored. Over time, the amount of stored triglycerides indicates the excess of energy intake over energy expenditure.

Even small differences add up over time. A gain of 20 pounds (9 kilograms) between ages 25 and 55 represents only a tiny imbalance, about 0.3% more energy intake in food than energy expenditure.

Regulation of Food Intake

Negative feedback mechanisms regulate both our energy intake and our energy expenditure. But no sensory receptors exist to monitor our weight or size. How then is food intake regulated? The answer to this question is incomplete, but important advances in understanding regulation of food intake have occurred in the past decade. It depends on many factors, including neural and endocrine signals, levels of certain nutrients in the blood, psychological elements such as stress or depression, signals from the digestive canal, and the special senses, and neural connections between the hypothalamus and other parts of the brain.

Within the hypothalamus are clusters of neurons that play key roles in regulating food intake. Satiety is a feeling of fullness accompanied by lack of desire to eat. Two hypothalamic areas involved in regulation of food intake are the arcuate nucleus and the paraventricular nucleus (see Figure 14.10). In 1994, the first experiments were reported on a mouse gene, named obese, that causes overeating and severe obesity in its mutated form. The product of this gene is the hormone leptin.

In both mice and humans, leptin helps decrease adiposity, total body-fat mass. Leptin is synthesized and secreted by adipocytes in proportion to adiposity; as more triglycerides are stored, more leptin is secreted into the bloodstream. Leptin acts on the hypothalamus to inhibit circuits that stimulate eating while also activating circuits that increase energy expenditure.

The hormone insulin has a similar but smaller effect. Both leptin and insulin are able to pass through the blood-brain barrier.

When leptin and insulin levels are low, neurons that extend from the arcuate nucleus to the paraventricular nucleus release a neurotransmitter called neuropeptide Y that stimulates food intake. Other neurons that extend between the arcuate and paraventricular nuclei release a neurotransmitter called melanocortin, which is similar to melanocyte-stimulating hormone M.S.H. Leptin stimulates release of melanocortin, which acts to inhibit food intake. Another hormone involved in the regulation of food intake is ghrelin, which is produced by endocrine cells of the stomach.

Ghrelin plays a role in increasing appetite. It is thought that ghrelin performs this function by stimulating the release of neuropeptide Y from hypothalamic neurons. Although leptin, neuropeptide Y, melanocortin, and ghrelin are key signaling molecules for maintaining energy balance, several other hormones and neurotransmitters also contribute.

Other areas of the hypothalamus plus nuclei in the brainstem, limbic system, and cerebral cortex take part. An understanding of the brain circuits involved is still far from complete.

Achieving energy balance requires regulation of energy intake. Most increases and decreases in food intake are due to changes in meal size rather than changes in number of meals. Many experiments have demonstrated the presence of satiety signals, chemical or neural changes that help terminate eating when “fullness” is attained. For example, an increase in blood glucose level, as occurs after a meal, decreases appetite. Several hormones, such as glucagon, cholecystokinin, estrogens, and epinephrine (acting via beta receptors) act to signal satiety and to increase energy expenditure.

Distension of the digestive canal, particularly the stomach and duodenum, also contributes to termination of food intake. Other hormones increase appetite and decrease energy expenditure. These include growth hormone-releasing hormone G.H.R.H, androgens, glucocorticoids, epinephrine (acting via alpha receptors), and progesterone.

Emotional Eating

In addition to keeping us alive, eating serves countless psychological, social, and cultural purposes. We eat to celebrate, punish, comfort, defy, and deny. Eating in response to emotional drives, such as feeling stressed, bored, or tired, is called emotional eating.

Emotional eating is so common that, within limits, it is considered well within the range of normal behavior. Who hasn't at one time or another headed for the refrigerator after a bad day? Problems arise when emotional eating becomes so excessive that it interferes with health.

Physical health problems include obesity and associated disorders such as hypertension and heart disease. Psychological health problems include poor self-esteem, an inability to cope effectively with feelings of stress, and in extreme cases, eating disorders such as anorexia nervosa, bulimia, and obesity.

Eating provides comfort and solace, numbing pain and “feeding the hungry heart.” Eating may provide a biochemical “fix” as well. Emotional eaters typically overeat carbohydrate foods (sweets and starches), which may raise brain serotonin levels and lead to feelings of relaxation. Food becomes a way to self-medicate when negative emotions arise.

Checkpoint

25. What is a calorie? Why is the kilocalorie often used more than the calorie to express the energy content of food?

26. What are the three components that contribute to the total metabolic rate?

27. What are the functions of leptin, neuropeptide Y, melanocortin, and ghrelin?

25.9 Regulation of Body Temperature

Objectives

• Describe the various mechanisms of heat transfer.

• Explain how normal body temperature is maintained by negative feedback loops involving the hypothalamic thermostat.

Your body produces more or less heat depending on the rates of its metabolic reactions. Because homeostasis of body temperature can be maintained only if the rate of heat loss from the body equals the rate of heat production by metabolism, it is important to understand the ways in which heat can be lost, gained, or conserved. Heat is a form of energy that can be measured as temperature. Despite wide fluctuations in environmental temperature, homeostatic mechanisms can maintain a normal range for internal body temperature. If the rate of body heat production equals the rate of heat loss, the body maintains a constant core temperature near 37 degrees Celsius 98.6 degrees Fahrenheit Core temperature is the temperature in body structures deep to the skin and subcutaneous tissue. Shell temperature is the temperature near the body surface—in the skin and subcutaneous tissue.

Depending on the environmental temperature, shell temperature is 1 to 6 degrees Celsius lower than core temperature. A core temperature that is too high kills by denaturing body proteins; a core temperature that is too low causes cardiac arrhythmias that result in death.

Mechanisms of Heat Transfer

Maintaining normal body temperature depends on the ability to lose heat to the environment at the same rate as it is produced by metabolic reactions. Heat can be transferred between the body and its surroundings in four ways: via conduction, convection, radiation, and evaporation.

1. Conduction is the heat exchange that occurs between molecules of two materials that are in direct contact with each other. At rest, about 3% of body heat is lost via conduction to cooler, solid materials in contact with the body, such as a chair, clothing, and jewelry. Heat can also be gained via conduction—for example, while soaking in a hot tub. Because water conducts heat 20 times more effectively than air, heat loss or heat gain via conduction is much greater when the body is submerged in cold or hot water.

2. Convection is the transfer of heat by the movement of air or water between areas of different temperatures. The contact of air or water with your body results in heat transfer by both conduction and convection. When cool air makes contact with the body, the air becomes warmed and therefore less dense and is carried away by convection currents created as the less dense air rises. The faster the air moves—for example, by a breeze or a fan—the faster the rate of convection. At rest, about 15% of body heat is lost to the air via conduction and convection.

3. Radiation is the transfer of heat in the form of infrared rays between a warmer object and a cooler one without physical contact. Your body loses heat by radiating more infrared waves than it absorbs from cooler objects. If surrounding objects are warmer than you are, you absorb more heat than you lose by radiation. In a room at 21 degrees Celsius 70 degrees Fahrenheit, about 60% of heat loss occurs via radiation in a resting person.

4. Evaporation is the conversion of a liquid to a vapor. Every milliliter of evaporating water takes with it a great deal of heat—about 0.58 kilocalories/mL. Under typical resting conditions, about 22% of heat loss occurs through evaporation of about 700 mL of water per day—300 mL in exhaled air and 400 mL from the skin surface. Because we are not normally aware of this water loss through the skin and mucous membranes of the mouth and respiratory system, it is termed insensible water loss. The rate of evaporation is inversely related to relative humidity, the ratio of the actual amount of moisture in the air to the maximum amount it can hold at a given temperature. The higher the relative humidity, the lower the rate of evaporation. At 100% humidity, heat is gained via condensation of water on the skin surface as fast as heat is lost via evaporation.

Evaporation provides the main defense against overheating during exercise. Under extreme conditions, a maximum of about 3 liters of sweat can be produced each hour, removing more than 1700 kilocalories of heat if all of it evaporates. (Note: Sweat that drips off the body rather than evaporating removes very little heat.)

Hypothalamic Thermostat

The control center that functions as the body's thermostat is a group of neurons in the anterior part of the hypothalamus, the preoptic area. This area receives input from thermoreceptors in the skin (peripheral thermoreceptors) and in the hypothalamus itself (central thermoreceptors). Neurons of the preoptic area generate nerve impulses at a higher frequency when blood temperature increases and at a lower frequency when blood temperature decreases.

Nerve impulses from the preoptic area propagate to two other parts of the hypothalamus known as the heat-losing center and the heat-promoting center, which, when stimulated by the preoptic area, set into operation a series of responses that lower body temperature and raise body temperature, respectively.

Thermoregulation

If core temperature declines, mechanisms that help conserve heat and increase heat production act via negative feedback to raise the body temperature to normal (Figure 25.19). Peripheral thermoreceptors and central thermoreceptors send input to the preoptic area of the hypothalamus, which in turn activates the heat-promoting center. In response, the hypothalamus discharges action potentials and secretes thyrotropin-releasing hormone T.R.H, which in turn stimulates thyrotrophic cells in the anterior pituitary gland to release thyroid-stimulating hormone (T.S.H). Nerve impulses from the hypothalamus and T.S.H then activate several effectors, which respond in the following ways to increase the core temperature to the normal value:

• Vasoconstriction. Nerve impulses from the heat-promoting center stimulate sympathetic nerves that cause blood vessels of the skin to constrict. Vasoconstriction decreases the flow of warm blood, and thus the transfer of heat, from the internal organs to the skin. Slowing the rate of heat loss allows the internal body temperature to increase as metabolic reactions continue to produce heat.

• Release of epinephrine and norepinephrine. Action potentials in sympathetic nerves leading to the suprarenal medulla stimulate the release of epinephrine and norepinephrine into the blood. The hormones in turn bring about an increase in cellular metabolism, which increases heat production.

• Shivering. The heat-promoting center stimulates parts of the brain that increase muscle tone and hence heat production. As muscle tone increases in one muscle (the agonist), the small contractions stretch muscle spindles in its antagonist, initiating a stretch reflex. The resulting contraction in the antagonist stretches muscle spindles in the agonist, and it too develops a stretch reflex.

This repetitive cycle—called shivering—greatly increases the rate of heat production. During maximal shivering, body heat production can rise to about four times the basal rate in just a few minutes.

• Release of thyroid hormones. The thyroid gland responds to T.S.H by releasing more thyroid hormones into the blood. As increased levels of thyroid hormones slowly increase the metabolic rate, body temperature rises.

If core body temperature rises above normal, a negative feedback loop opposite to the one depicted in Figure 25.19 goes into action. The higher temperature of the blood stimulates peripheral and central thermoreceptors that send input to the preoptic area, which in turn stimulates the heat-losing center and inhibits the heat-promoting center. Nerve impulses from the heat-losing center cause dilation of blood vessels in the skin.

The skin becomes warm, and the excess heat is lost to the environment via radiation and conduction as an increased volume of blood flows from the warmer core of the body into the cooler skin. At the same time, metabolic rate decreases, and shivering does not occur. The high temperature of the blood stimulates sweat glands of the skin via hypothalamic activation of sympathetic nerves.

As the water in perspiration evaporates from the surface of the skin, the skin is cooled. All of these responses counteract heat-promoting effects and help return body temperature to normal.

Clinical Connection

Hypothermia

Hypothermia hypothermia is a lowering of core body temperature to 35 degrees Celsius 95 degrees Fahrenheit or below. Causes of hypothermia include an overwhelming cold stress (immersion in icy water), metabolic diseases (hypoglycemia, suprarenal insufficiency, or hypothyroidism), drugs (alcohol, antidepressants, sedatives, or tranquilizers), burns, and malnutrition. Hypothermia is characterized by the following as core body temperature falls: sensation of cold, shivering, confusion, vasoconstriction, muscle rigidity, bradycardia, acidosis, hypoventilation, hypotension, loss of spontaneous movement, coma, and death (usually caused by cardiac arrhythmias). Because the elderly have reduced metabolic protection against a cold environment coupled with a reduced perception of cold, they are at greater risk for developing hypothermia.

Figure 25.19 Negative Feedback Mechanisms That Conserve Heat and Increase Heat Production.

Core temperature is the temperature in body structures deep to the skin and subcutaneous tissue; shell temperature is the temperature near the body surface.

28. Distinguish between core temperature and shell temperature.

29. In what ways can a person lose heat to or gain heat from the surroundings? How is it possible for a person to lose heat on a sunny beach when the temperature is 40 degrees Celsius 104 degrees Fahrenheit and the humidity is 85%?

30. Describe how each of the following parts of the hypothalamus plays a role in thermoregulation: preoptic area, heat-promoting center, and heat-losing center.

25.10 Nutrition

Objectives

• Describe how to select foods to maintain a healthy diet.

- Compare the sources, functions, and importance of minerals and vitamins in metabolism.

Nutrients are chemical substances in food that body cells use for growth, maintenance, and repair. The six main types of nutrients are water, carbohydrates, lipids, proteins, minerals, and vitamins. Water is the nutrient needed in the largest amount—about 2 to 3 liters per day.

As the most abundant compound in the body, water provides the medium in which most metabolic reactions occur, and it also participates in some reactions (for example, hydrolysis reactions). The important roles of water in the body can be reviewed in Section 2.4. Three organic nutrients—carbohydrates, lipids, and proteins—provide the energy needed for metabolic reactions and serve as building blocks to make body structures. Some minerals and many vitamins are components of the enzyme systems that catalyze metabolic reactions.

Essential nutrients are specific nutrient molecules that the body cannot make in sufficient quantity to meet its needs and thus must be obtained from the diet. Some amino acids, fatty acids, vitamins, and minerals are essential nutrients.

Next, we discuss some guidelines for healthy eating and the roles of minerals and vitamins in metabolism.

Guidelines for Healthy Eating

Each gram of protein or carbohydrate in food provides about 4 Calories; 1 gram of fat (lipids) provides about 9 Calories. We do not know with certainty what levels and types of carbohydrate, fat, and protein are optimal in the diet. Different populations around the world eat radically different diets that are adapted to their particular lifestyles. However, many experts recommend the following distribution of calories: 50 to 60% from carbohydrates, with less than 15% from simple sugars; less than

Figure 25.20 MyPlate.

The different colored sections are meant to be visual cues to help make healthier eating choices.

30% from fats (triglycerides are the main type of dietary fat), with no more than 10% as saturated fats; and about 12 to 15% from proteins.

In 2011, the United States Department of Agriculture (U.S.D.A) introduced a revised icon called MyPlate based on revised guidelines for healthy eating. It replaces the U.S.D.A MyPyramid, which first appeared in 2005. As shown in Figure 25.20, the plate is divided into four different-sized colored sections:

Figure 25.20 summary: This figure is a conceptual diagram representing a dietary guide. It depicts a plate divided into sections for different food groups, including fruits, vegetables, grains, and protein, accompanied by a separate small circle for dairy. The diagram suggests a balanced diet where vegetables and grains occupy significant portions of the plate, while fruits and proteins make up smaller, roughly equal shares, with dairy serving as a complementary addition.

• Green (vegetables)

• Red (fruits)

• Orange (grains)

• Purple (protein)

The blue cup (dairy) adjacent to the plate icon is a reminder to include three daily servings of dairy.

The Dietary Guidelines for Americans released in January 2011 are the basis of MyPlate. Among the guidelines are the following:

• Enjoy food but balance calories by eating less.

• Avoid oversized portions, and make half of your plate vegetables and fruits.

• Switch to fat-free or low-fat milk.

• Make at least half of your grains whole grains.

• Choose foods that have a lower sodium content.

• Drink water instead of sugary drinks.

MyPlate places of a lot of emphasis on proportionality, variety, moderation, and nutrient density in a healthy diet. Proportionality simply means eating more of some types of foods than others. The MyPlate icon shows how much of your plate should be filled with foods from various food groups.

Note that the vegetables and fruits take up one half of the plate, while protein and grains take up the other half. Note also that vegetables and grains represent the largest portions.

Variety is important for a healthy diet because no one food or food group provides all of the nutrients and food types that the body needs. Accordingly, a variety of foods should be selected from within each food group. Vegetable choices should be varied to include dark green vegetables such as broccoli, collard greens, and kale; red and orange vegetables such as carrots, sweet potatoes, and red peppers; starchy vegetables such as corn, green peas, and potatoes; other vegetables such as cabbage, asparagus, and artichokes; and beans and peas such as lentils, chickpeas, and black beans.

Beans and peas are good sources of the nutrients found in both vegetables and protein foods so they can be counted in either food group. Protein food choices are extremely varied, and include meat, poultry, seafood, beans and peas, eggs, processed soy products, nuts, and seeds. Grains include whole grains such as whole-wheat bread, oatmeal, and brown rice as well as refined grains such as white bread, white rice, and white pasta.

Fruits include fresh, canned, or dried fruit and 100% fruit juice. Dairy includes all fluid milk products and many foods made from milk such as cheese, yogurt, and pudding, as well as calcium-fortified soy products.

Choosing nutrient-dense foods helps individuals practice moderation to balance calories consumed with calories expended. Tips include making half of your grains whole grains, choosing whole or cut-up fruits more often than juice, selecting fat-free or low-fat dairy products, and keeping meat and poultry portions small and lean.

Minerals

Minerals are inorganic elements that occur naturally in the earth's crust. In the body they appear in combination with one another, in combination with organic compounds, or as ions in solution. Minerals constitute about 4% of total body mass and are concentrated most heavily in the skeleton. Minerals with known functions in the body include calcium, phosphorus, potassium, sulfur, sodium, chloride, magnesium, iron, iodide, manganese, copper, cobalt, zinc, fluoride, selenium, and chromium.

Table 25.9 describes the vital functions of these minerals. Note that the body generally uses the ions of the minerals rather than the non-ionized form. Some minerals, such as chlorine, are toxic or even fatal if ingested in the non-ionized form.

Table 25.9 summary: This table outlines various minerals vital to the body, detailing their primary dietary sources, methods of excretion, and biological importance. It distinguishes between major minerals, such as calcium and phosphorus which are heavily concentrated in bones and teeth, and trace minerals like cobalt and chromium. The functions described range from structural support and fluid balance to critical roles in nerve conduction, hormone synthesis, and enzymatic activity.

Other minerals—aluminum, boron, silicon, and molybdenum—are present but their functions are unclear. Typical diets supply adequate amounts of potassium, sodium, chloride, and magnesium. Some attention must be paid to eating foods that provide enough calcium, phosphorus, iron, and iodide.

Excess amounts of most minerals are excreted in the urine and feces.

Calcium and phosphorus form part of the matrix of bone. Because minerals do not form long-chain compounds, they are otherwise poor building materials. A major role of minerals is to help regulate enzymatic reactions. Calcium, iron, magnesium, and manganese are constituents of some coenzymes.

Magnesium also serves as a catalyst for the conversion of A.D.P to A.T.P. Minerals such as sodium and phosphorus work in buffer systems, which help control the pH of body fluids. Sodium also helps regulate the osmosis of water and, along with other ions, is involved in the generation of nerve impulses.

Vitamins

Organic nutrients required in small amounts to maintain growth and normal metabolism are called vitamins. Unlike carbohydrates, lipids, or proteins, vitamins do not provide energy or serve as the body's building materials. Most vitamins with known functions are coenzymes.

Most vitamins cannot be synthesized by the body and must be ingested in food. Other vitamins, such as vitamin K, are produced by bacteria in the digestive canal and then absorbed. The body can assemble some vitamins if the raw materials, called provitamins, are provided. For example, vitamin A is produced by the body from the provitamin beta-carotene, a chemical present in yellow vegetables such as carrots and in dark green vegetables such as spinach. No single food contains all of the required vitamins—one of the best reasons to eat a varied diet.

Vitamins are divided into two main groups: fat-soluble and water-soluble. The fat-soluble vitamins, vitamins A, D, E, and K, are absorbed along with other dietary lipids in the small intestine and packaged into chylomicrons. They cannot be absorbed in adequate quantity unless they are ingested with other lipids.

Fat-soluble vitamins may be stored in cells, particularly hepatocytes. The water-soluble vitamins, including several B vitamins and vitamin C, are dissolved in body fluids. Excess quantities of these vitamins are not stored but instead are excreted in the urine.

In addition to their other functions, three vitamins—C, E, and beta-carotene (a provitamin)—are termed antioxidant vitamins because they inactivate oxygen-free radicals. Recall that free radicals are highly reactive ions or molecules that carry an unpaired electron in their outermost electron shell (see Figure 2.3). Free radicals damage cell membranes, D.N.A, and other cellular structures and contribute to the formation of artery-narrowing atherosclerotic plaques. Some free radicals arise naturally in the body, and others come from environmental hazards such as tobacco smoke and radiation.

Antioxidant vitamins are thought to play a role in protecting against some kinds of cancer, reducing the buildup of atherosclerotic plaque, delaying some effects of aging, and decreasing the chance of cataract formation in the lens of the eyes. Table 25.10 lists the major vitamins, their sources, their functions, and related deficiency disorders.

Table 25.10 summary: This table provides a comprehensive overview of principal vitamins, categorized by their solubility into fat-soluble and water-soluble groups. For each vitamin, it details the dietary sources and biological origins, the primary physiological functions—such as acting as coenzymes in metabolism, supporting cell structure, or regulating mineral homeostasis—and the specific clinical symptoms and disorders that arise from their deficiency, ranging from vision loss and skeletal deformities to various forms of anemia and neurological impairments.

Vitamin and Mineral Supplements

Most nutritionists recommend eating a balanced diet that includes a variety of foods rather than taking vitamin or mineral supplements, except in special circumstances. Common examples of necessary supplementation include iron for women who have excessive menstrual bleeding; iron and calcium for women who are pregnant or breast-feeding; folic acid for all women who may become pregnant, to reduce the risk of fetal neural tube defects; calcium for most adults, because they do not receive the recommended amount in their diets; and vitamin B 12 for strict vegetarians, who eat no meat. Because high levels of antioxidant vitamins are thought to have beneficial effects, some experts recommend supplementing vitamins C and E. More is not always better, however; larger doses of vitamins or minerals can be very harmful.

Hypervitaminosis (hi-per-vi-ta-mi-NÖ-sis; hyper-= too much or above) refers to dietary intake of a vitamin that exceeds the ability of the body to utilize, store, or excrete the vitamin. Since water-soluble vitamins are not stored in the body, few cause any problems. However, because lipid-soluble vitamins are stored in the body, excessive consumption may cause problems.

For example, excess intake of vitamin A can cause drowsiness, general weakness, irritability, headache, vomiting, dry and peeling skin, partial hair loss, joint pain, liver and spleen enlargement, coma, and even death. Hypovitaminosis (hypo-= too little or below), or vitamin deficiency, is discussed in Table 25.10 for the various vitamins.

Checkpoint

33. What is a mineral? Briefly describe the functions of the following minerals: calcium, phosphorus, potassium, sulfur, sodium, chloride, magnesium, iron, iodine, copper, zinc, fluoride, manganese, cobalt, chromium, and selenium.

34. Define vitamin. Explain how we obtain vitamins. Distinguish between a fat-soluble vitamin and a water-soluble vitamin.

35. For each of the following vitamins, indicate its principal function and the effect(s) of deficiency: A, D, E, K, B₁, B₂, niacin, B₆, B₁₂, pantothenic acid, folic acid, biotin, and C.

Disorders: Homeostatic Imbalances

Anorexia Nervosa

Anorexia nervosa is a chronic disorder characterized by self-induced weight loss, negative perception of body image, and physiological changes that result from nutritional depletion.

Patients with anorexia nervosa have a fixation on weight control and often insist on having a bowel movement every day despite inadequate food intake. They often abuse laxatives, which worsens the fluid and electrolyte imbalances and nutrient deficiencies. The disorder is found predominantly in young, single females, and it may be inherited. Abnormal patterns of menstruation, amenorrhea (absence of menstruation), and a lowered basal metabolic rate reflect the depressant effects of starvation. Individuals may become emaciated and may ultimately die of starvation or one of its complications.

Also associated with the disorder are osteoporosis, depression, and brain abnormalities coupled with impaired mental performance. Treatment consists of psychotherapy and dietary regulation.

Fever

A fever is an elevation of core temperature caused by a resetting of the hypothalamic thermostat. The most common causes of fever are viral or bacterial infections and bacterial toxins; other causes are ovulation, excessive secretion of thyroid hormones, tumors, and reactions to vaccines. When phagocytes ingest certain bacteria, they are stimulated to secrete a pyrogen (Pi-rogen; pyro-= fire; -gen = produce), a fever-producing substance. One pyrogen is interleukin-1. It circulates to the hypothalamus and induces neurons of the preoptic area to secrete prostaglandins.

Some prostaglandins can reset the hypothalamic thermostat at a higher temperature, and temperature-regulating reflex mechanisms then act to bring the core body temperature up to this new setting. Antipyretics are agents that relieve or reduce fever. Examples include aspirin, acetaminophen (Tylenol), and ibuprofen (Advil), all of which reduce fever by inhibiting synthesis of certain prostaglandins.

Suppose that due to production of pyrogens the thermostat is reset at 39 superscript circle C ( 103 superscript circle F). Now the heat-promoting mechanisms (vasoconstriction, increased metabolism, shivering) are operating at full force. Thus, even though core temperature is climbing higher than normal—say, 38 superscript circle C ( 101 superscript circle F)—the skin remains cold, and shivering occurs. This condition, called a chill, is a definite sign that core temperature is rising. After several hours, core temperature reaches the setting of the thermostat, and the chills disappear.

But now the body will continue to regulate temperature at 39 superscript circle C ( 103 superscript circle F). When the pyrogens disappear, the thermostat is reset at normal— 37.0 superscript circle C ( 98.6 superscript circle F). Because core temperature is high in the beginning, the heat-losing mechanisms (vasodilation and sweating) go into operation to decrease core temperature. The skin becomes warm, and the person begins to sweat. This phase of the fever is called the crisis, and it indicates that core temperature is falling.

Although death results if core temperature rises above 44 to 46 degrees Celsius (112 to 114 degrees Fahrenheit, up to a point, fever is beneficial. For example, a higher temperature intensifies the effects of interferons and the phagocytic activities of macrophages while hindering replication of some pathogens. Because fever increases heart rate, infection-fighting white blood cells are delivered to sites of infection more rapidly. In addition, antibody production and T cell proliferation increase. Moreover, heat speeds up the rate of chemical reactions, which may help body cells repair themselves more quickly.

Obesity

Obesity is body weight more than 20% above a desirable standard due to an excessive accumulation of adipose tissue. More than one-third of the adult population in the United States is obese. (An athlete may be overweight due to higher-than-normal amounts of muscle tissue without being obese.) Even moderate obesity is hazardous to health; it is a risk factor in cardiovascular disease, hypertension, pulmonary disease, non-insulin-dependent diabetes mellitus, arthritis, certain cancers (breast, uterus, and colon), varicose veins, and gallbladder disease.

In a few cases, obesity may result from trauma of or tumors in the food-regulating centers in the hypothalamus. In most cases of obesity, no specific cause can be identified. Contributing factors include genetic factors, eating habits taught early in life, overeating to relieve tension, and social customs. Studies indicate that some obese people burn fewer calories during digestion and absorption of a meal, a smaller food-induced thermogenesis effect.

Additionally, obese people who lose weight require about 15% fewer calories to maintain normal body weight than do people who have never been obese. Interestingly, people who gain weight easily when deliberately fed excess calories exhibit less neat (nonexercise activity thermogenesis, such as occurs with fidgeting) than people who resist weight gains in the face of excess calories. Although leptin suppresses appetite and produces satiety in experimental animals, it is not deficient in most obese people.

Most surplus calories in the diet are converted to triglycerides and stored in adipose cells. Initially, the adipocytes increase in size, but at a maximal size, they divide. As a result, proliferation of adipocytes occurs in extreme obesity. The

Medical Terminology

Bulimia bulimia; bu-= ox; -limia = hunger) or binge-purge syndrome A disorder that typically affects young, single, middle-class white females, characterized by overeating at least twice a week followed by purging by self-induced vomiting, strict dieting or fasting, vigorous exercise, or use of laxatives or diuretics; it occurs in response to fears of being overweight or to stress, depression, and physiological disorders such as hypothalamic tumors.

Heat cramps Cramps that result from profuse sweating. The salt lost in sweat causes painful contractions of muscles; such cramps tend to occur in muscles used while working but do not appear until the person relaxes once the work is done. Drinking salted liquids usually leads to rapid improvement.

Heat exhaustion (heat prostration) A condition in which the core temperature is generally normal, or a little below, and the skin is cool and moist due to profuse perspiration. Heat exhaustion is usually characterized by loss of fluid and electrolytes, especially salt (N-A-C-L). The salt loss results in muscle cramps, dizziness, vomiting, and fainting; fluid loss may cause low blood pressure. Complete rest, rehydration, and electrolyte replacement are recommended.

Heatstroke (sunstroke) A severe and often fatal disorder caused by exposure to high temperatures, especially when the relative enzyme endothelial lipoprotein lipase regulates triglyceride storage. The enzyme is very active in abdominal fat but less active in hip fat. Accumulation of fat in the abdomen is associated with higher blood cholesterol level and other cardiac risk factors because adipose cells in this area appear to be more metabolically active.

Treatment of obesity is difficult because most people who are successful at losing weight gain it back within 2 years. Yet even modest weight loss is associated with health benefits. Treatments for obesity include behavior modification programs, very-low-calorie diets, drugs, and surgery. Behavior modification programs, offered at many hospitals, strive to alter eating behaviors and increase exercise activity.

The nutrition program includes a “heart-healthy” diet that includes abundant vegetables but is low in fats, especially saturated fats. A typical exercise program suggests walking for 30 minutes a day, five to seven times a week. Regular exercise enhances both weight loss and weight-loss maintenance. Very-low-calorie (V.L.C) diets include 400 to 800 kilocalories/day in a commercially made liquid mixture.

The V.L.C diet is usually prescribed for 12 weeks, under close medical supervision. Two drugs are available to treat obesity. Sibutramine is an appetite suppressant that works by inhibiting reuptake of serotonin and norepinephrine in brain areas that govern eating behavior.

Orlistat works by inhibiting the lipases released into the lumen of the digestive canal. With less lipase activity, fewer dietary triglycerides are absorbed. For those with extreme obesity who have not responded to other treatments, a surgical procedure may be considered. The two operations most commonly performed—gastric bypass and gastroplasty—both greatly reduce the stomach size so that it can hold just a tiny quantity of food. humidity is high, which makes it difficult for the body to lose heat. Blood flow to the skin is decreased, perspiration is greatly reduced, and body temperature rises sharply because of failure of the hypothalamic thermostat. Body temperature may reach 43 degrees Celsius 110 degrees Fahrenheit. Treatment, which must be undertaken immediately, consists of cooling the body by immersing the victim in cool water and by administering fluids and electrolytes.

Kwashiorkor kwashiorkor A disorder in which protein intake is deficient despite normal or nearly normal caloric intake, characterized by edema of the abdomen, enlarged liver, decreased blood pressure, low pulse rate, lower-than-normal body temperature, and sometimes mental retardation. Because the main protein in corn (zein) lacks two essential amino acids, which are needed for growth and tissue repair, many African children whose diet consists largely of cornmeal develop kwashiorkor.

Malnutrition (mal-= bad) An imbalance of total caloric intake or intake of specific nutrients, which can be either inadequate or excessive.

Marasmus marasmus A type of protein-calorie undernutrition that results from inadequate intake of both protein and calories. Its characteristics include retarded growth, low weight, muscle wasting, emaciation, dry skin, and thin, dry, dull hair.

Chapter Review

Review

Introduction

1. Our only source of energy for performing biological work is the food we eat. Food also provides essential substances that we cannot synthesize.

2. Most food molecules absorbed by the digestive canal are used to supply energy for life processes, serve as building blocks during synthesis of complex molecules, or are stored for future use.

25.1 Metabolic Reactions

1. Metabolism refers to all chemical reactions of the body and is of two types: catabolism and anabolism.

2. Catabolism is the term for reactions that break down complex organic compounds into simple ones. Overall, catabolic reactions are exergonic; they produce more energy than they consume.

3. Chemical reactions that combine simple molecules into more complex ones that form the body's structural and functional components are collectively known as anabolism. Overall, anabolic reactions are endergonic; they consume more energy than they produce.

4. The coupling of anabolism and catabolism occurs via A.T.P.

25.2 Energy Transfer

1. Oxidation is the removal of electrons from a substance; reduction is the addition of electrons to a substance.

2. Two coenzymes that carry hydrogen atoms during coupled oxidation-reduction reactions are nicotinamide adenine dinucleotide (N.A.D) and flavin adenine dinucleotide (F.A.D).

3. A.T.P can be generated via substrate-level phosphorylation, oxidative phosphorylation, and photophosphorylation.

25.3 Carbohydrate Metabolism

1. During digestion, polysaccharides and disaccharides are hydrolyzed into the monosaccharides glucose (about 80%), fructose, and galactose; the latter two are then converted to glucose. Some glucose is oxidized by cells to provide A.T.P. Glucose also can be used to synthesize amino acids, glycogen, and triglycerides.

2. Glucose moves into most body cells via facilitated diffusion through glucose transporters (GluT) and becomes phosphorylated to glucose 6-phosphate. In muscle cells, this process is stimulated by insulin. Glucose entry into neurons and hepatocytes is always “turned on.”

3. Cellular respiration, the complete oxidation of glucose to C-O₂ and H₂O, involves glycolysis, the Krebs cycle, and the electron transport chain.

4. Glycolysis is the breakdown of glucose into two molecules of pyruvic acid; there is a net production of two molecules of A.T.P.

5. When oxygen is in short supply, pyruvic acid is reduced to lactic acid; under aerobic conditions, pyruvic acid enters the Krebs cycle. Pyruvic acid is prepared for entrance into the Krebs cycle by conversion to a 2-carbon acetyl group followed by the addition of coenzyme A to form acetyl coenzyme A. The Krebs cycle involves decarboxylations, oxidations, and reductions of various organic acids. Each molecule of pyruvic acid that is converted to acetyl coenzyme A and then enters the Krebs cycle produces three molecules of C-O 2 , four molecules of N.A.D.H.

and four H⁺, one molecule of F.A.D.H₂, and one molecule of A.T.P. The energy originally stored in glucose and then in pyruvic acid is transferred primarily to the reduced coenzymes N.A.D.H and F.A.D.H₂.

6. The electron transport chain involves a series of oxidation-reduction reactions in which the energy in N.A.D.H and F.A.D.H 2 is liberated and transferred to A.T.P. The electron carriers include F.M.N, cytochromes, iron-sulfur centers, copper atoms, and coenzyme Q. The electron transport chain yields a maximum of 26 or 28 molecules of A.T.P and six molecules of H 2O .

7. Table 25.1 summarizes the A.T.P yield during cellular respiration. The complete oxidation of glucose can be represented as follows:

Math summary: This equation calculates the total energy yield from the complete oxidation of glucose. It processes glucose, oxygen, and adenosine diphosphate as inputs to produce carbon dioxide, water, and a net gain of thirty to thirty two adenosine triphosphate molecules as the final output.

8. The conversion of glucose to glycogen for storage in the liver and skeletal muscle is called glycogenesis. It is stimulated by insulin.

9. The conversion of glycogen to glucose is called glycogenolysis. It occurs between meals and is stimulated by glucagon and epinephrine.

10. Gluconeogenesis is the conversion of noncarbohydrate molecules into glucose. It is stimulated by cortisol and glucagon.

25.4 Lipid Metabolism

1. Lipoproteins transport lipids in the bloodstream. Types of lipoproteins include chylomicrons, which carry dietary lipids to adipose tissue; very-low-density lipoproteins V.L.D.L's, which carry triglycerides from the liver to adipose tissue; low-density lipoproteins L.D.L's, which deliver cholesterol to body cells; and high-density lipoproteins H.D.L's, which remove excess cholesterol from body cells and transport it to the liver for elimination.

2. Cholesterol in the blood comes from two sources: from food and from synthesis by the liver.

3. Lipids may be oxidized to produce A.T.P or stored as triglycerides in adipose tissue, mostly in the subcutaneous tissue.

4. A few lipids are used as structural molecules or to synthesize essential molecules.

5. Adipose tissue contains lipases that catalyze the deposition of triglycerides from chylomicrons and hydrolyze triglycerides into fatty acids and glycerol.

6. In lipolysis, triglycerides are split into fatty acids and glycerol and released from adipose tissue under the influence of epinephrine, norepinephrine, cortisol, thyroid hormones, and insulinlike growth factors.

7. Glycerol can be converted into glucose by conversion into glyceraldehyde 3-phosphate.

8. In beta oxidation of fatty acids, carbon atoms are removed in pairs from fatty acid chains; the resulting molecules of acetyl coenzyme A enter the Krebs cycle.

9. The conversion of glucose or amino acids into lipids is called lipogenesis; it is stimulated by insulin.

25.5 Protein Metabolism

1. During digestion, proteins are hydrolyzed into amino acids, which enter the liver via the hepatic portal vein.

2. Amino acids, under the influence of insulin-like growth factors and insulin, enter body cells via active transport.

3. Inside cells, amino acids are synthesized into proteins that function as enzymes, hormones, structural elements, and so forth; are stored as fat or glycogen; or are used for energy.

4. Before amino acids can be catabolized, they must be deaminated and converted to substances that can enter the Krebs cycle.

5. Amino acids may also be converted into glucose, fatty acids, and ketone bodies.

6. Protein synthesis is stimulated by insulin-like growth factors, thyroid hormones, insulin, estrogens, and testosterone.

7. Table 25.2 summarizes carbohydrate, lipid, and protein metabolism.

25.6 Key Molecules at Metabolic Crossroads

1. Three molecules play a key role in metabolism: glucose 6-phosphate, pyruvic acid, and acetyl coenzyme A.

2. Glucose 6-phosphate may be converted to glucose, glycogen, ribose 5-phosphate, and pyruvic acid.

3. When A.T.P is low and oxygen is plentiful, pyruvic acid is converted to acetyl coenzyme A; when oxygen supply is low, pyruvic acid is converted to lactic acid. Carbohydrate and protein metabolism are linked by pyruvic acid.

4. Acetyl coenzyme A is the molecule that enters the Krebs cycle; it is also used to synthesize fatty acids, ketone bodies, and cholesterol.

25.7 Metabolic Adaptations

1. During the absorptive state, ingested nutrients enter the blood and lymph from the digestive canal.

2. During the absorptive state, blood glucose is oxidized to form A.T.P, and glucose transported to the liver is converted to glycogen or triglycerides. Most triglycerides are stored in adipose tissue. Amino acids in hepatocytes are converted to carbohydrates, fats, and proteins. Table 25.3 summarizes the hormonal regulation of metabolism during the absorptive state.

3. During the postabsorptive state, absorption is complete and the A.T.P needs of the body are satisfied by nutrients already present in the body. The major task is to maintain normal blood glucose level by converting glycogen in the liver and skeletal muscle into glucose, converting glycerol into glucose, and converting amino acids into glucose. Fatty acids, ketone bodies, and amino acids are oxidized to supply A.T.P. Table 25.4 summarizes the hormonal regulation of metabolism during the postabsorptive state.

4. Fasting is going without food for a few days; starvation implies weeks or months of inadequate food intake. During fasting and starvation, fatty acids and ketone bodies are increasingly utilized for A.T.P production.

25.8 Energy Balance

1. Energy balance is the precise matching of energy intake to energy expenditure over time.

2. A calorie (cal) is the amount of energy required to raise the temperature of 1 g of water 1 degree Celsius. Because the calorie is a relatively small unit, the kilocalorie (kilocalories) or Calorie (Cal) is often used to measure the body's metabolic rate and to express the energy content of foods; a kilocalorie equals 1000 calories.

3. Metabolic rate is the overall rate at which metabolic reactions use energy. Factors that affect metabolic rate include hormones, exercise, the nervous system, body temperature, ingestion of food, age, gender, climate, sleep, and malnutrition.

4. Measurement of the metabolic rate under basal conditions is called the basal metabolic rate (B.M.R).

5. Total metabolic rate (T.M.R) is the total energy expenditure by the body per unit time. Three components contribute to the T.M.R: (1) B.M.R, (2) physical activity, and (3) food-induced thermogenesis.

6. Adipose tissue is the major site of stored chemical energy.

7. Two nuclei in the hypothalamus that help regulate food intake are the arcuate and paraventricular nuclei. The hormone leptin, released by adipocytes, inhibits release of neuropeptide Y from the arcuate nucleus and thereby decreases food intake. Melanocortin also decreases food intake. Ghrelin, released by the stomach, increases appetite by stimulating the release of neuropeptide Y.

25.9 Regulation of Body Temperature

1. Normal core temperature is maintained by a delicate balance between heat-producing and heat-losing mechanisms.

2. Mechanisms of heat transfer include conduction, convection, radiation, and evaporation. Conduction is the transfer of heat between two substances or objects in contact with each other. Convection is the transfer of heat by movement of air or water between areas of different temperatures. Radiation is the transfer of heat from a warmer object to a cooler object without physical contact. Evaporation is the conversion of a liquid to a vapor; in the process, heat is lost.

3. The hypothalamic thermostat is in the preoptic area.

4. Responses that produce, conserve, or retain heat when core temperature falls include vasoconstriction; release of epinephrine and norepinephrine; shivering; and release of thyroid hormones.

5. Responses that increase heat loss when core temperature increases include vasodilation, decreased metabolic rate, and evaporation of perspiration.

25.10 Nutrition

1. Nutrients include water, carbohydrates, lipids, proteins, minerals, and vitamins.

2. Nutrition experts suggest dietary calories be 50 to 60% from carbohydrates, 30% or less from fats, and 12 to 15% from proteins.

3. MyPlate emphasizes proportionality, variety, moderation, and nutrient density. In a healthy diet vegetables and fruits take up half the plate, while protein and grains take up the other half. Vegetables and grains represent the largest portion. Three servings of dairy per day are also recommended.

4. Minerals known to perform essential functions include calcium, phosphorus, potassium, sulfur, sodium, chloride, magnesium, iron, iodide, manganese, copper, cobalt, zinc, fluoride, selenium, and chromium. Their functions are summarized in Table 25.9.

5. Vitamins are organic nutrients that maintain growth and normal metabolism. Many function in enzyme systems.

6. Fat-soluble vitamins are absorbed with fats and include vitamins A, D, E, and K; water-soluble vitamins include the B vitamins and vitamin C.

7. The functions and deficiency disorders of the principal vitamins are summarized in Table 25.1.

Critical Thinking Questions

1. Jane Doe's deceased body was found at her dining room table. Her death was considered suspicious. Lab results from the medical investigation revealed cyanide in her blood. How did the cyanide cause her death?

2. During a recent physical, 55-year-old Glenn's blood serum lab results showed the following: total cholesterol = 300 milligrams/dL; L.D.L = 175 milligrams/dL; H.D.L = 20 milligrams/dL. Interpret these results for Glenn and indicate

Answers to Figure Questions

25.1 In pancreatic acinar cells, anabolism predominates because the primary activity is synthesis of complex molecules (digestive enzymes).

25.2 The electron transport chain produces the most A.T.P.

25.3 The reactions of glycolysis consume two molecules of A.T.P but generate four molecules of A.T.P, for a net gain of two.

25.4 Kinases are enzymes that phosphorylate (add phosphate to) their substrate.

25.5 Glycolysis occurs in the cytosol.

25.6 C-O 2 is given off during the production of acetyl coenzyme A and during the Krebs cycle. It diffuses into the blood, is transported by the blood to the lungs, and is exhaled.

25.7 The production of reduced coenzymes is important in the Krebs cycle because they will subsequently yield A.T.P in the electron transport chain.

25.8 The energy source that powers the proton pumps is electrons provided by N.A.D.H + H ^{+} .

25.9 The concentration of H superscript plus is highest in the space between the inner and outer mitochondrial membranes.

25.10 During the complete oxidation of one glucose molecule, six molecules of O 2 are used and six molecules of C O 2 are produced. to him what changes, if any, he needs to make in his lifestyle. Why are these changes important?

3. Marissa has joined a weight loss program. As part of the program, she regularly submits a urine sample which is tested for ketones. She went to the clinic today, had her urine checked, and was confronted by the nurse who accused Marissa of “cheating” on her diet. How did the nurse know Marissa was not following her diet?

25.11 Skeletal muscle fibers can synthesize glycogen, but they cannot release glucose into the blood because they lack the enzyme phosphatase required to remove the phosphate group from glucose.

25.12 Hepatocytes can carry out gluconeogenesis and glycogenesis.

25.13 L.D.L's deliver cholesterol to body cells.

25.14 Hepatocytes and adipose cells carry out lipogenesis, beta oxidation, and lipolysis; hepatocytes carry out ketogenesis.

25.15 Before an amino acid can enter the Krebs cycle, an amino group must be removed via deamination.

25.16 Acetyl coenzyme A is the gateway into the Krebs cycle for molecules being oxidized to generate A.T.P.

25.17 Reactions of the absorptive state are mainly anabolic.

25.18 Processes that directly elevate blood glucose during the postabsorptive state include lipolysis (in adipocytes and hepatocytes), gluconeogenesis (in hepatocytes), and glycogenolysis (in hepatocytes).

25.19 Exercise, the sympathetic nervous system, hormones (epinephrine, norepinephrine, thyroxine, testosterone, growth hormone), elevated body temperature, and ingestion of food increase metabolic rate, which results in an increase in body temperature.

25.20 The blue cup is a reminder to include three daily servings of dairy such as milk, yogurt, and cheese.

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