Medical Physiology, 3rd Edition

Forms of Energy

Virtually all energy that sustains humans derives, directly or indirectly, from breaking and releasing the energy stored in carbon-carbon bonds that were created in plants during photosynthesis. Cellulose, the principal form of this stored energy in the biosphere, consists of polymers of glucose joined by β-1,4 linkages that humans cannot digest (see pp. 914–915). However, ruminants can degrade cellulose to glucose because they have cellulase-producing bacteria in their digestive tracts. Humans obtain their energy from food in three forms: (1) carbohydrates, (2) proteins, and (3) lipids. Moreover, each form consists of building blocks: monosaccharides (glucose, fructose, and galactose) for carbohydrates, amino acids for proteins, and fatty acids for lipids.

Carbohydrates, which exist in the body mainly in the form of glucose, contain 4.1 kcal/g of energy. The major storage form is glycogen, a polymer of glucose (106 to 108 Da) that consists of glucose molecules linked together by α-1,4 linkages in the straight portions of the polymer (Fig. 58-1) and by α-1,6 linkages at the frequent branch points (see Fig. 45-3). Virtually all cells of the body store glycogen; the highest concentrations occur in liver and muscle. Cells store glycogen in cytoplasmic granules that also contain the enzymes needed for glycogen synthesis and degradation. Glycogen is highly hydrophilic, containing 1 to 2 g of water per gram of glycogen, and thus provides a handy storage depot for glucose without affecting the osmotic pressure of the intracellular space. However, this packaging of glycogen with water makes glycogen a relatively inefficient means of storing energy because it yields only 1 to 2 kcal for each gram of hydrated glycogen instead of the theoretical 4.1 kcal/g of dry carbohydrate. In contrast to the other potential stored forms of energy (lipid and protein), the liver can quickly break down glycogen by glycogenolysis to provide glucose for the brain during hypoglycemia. Similarly, muscle can quickly break down glycogen to glucose-6-phosphate (G6P) to provide the energy necessary to run a high-intensity anaerobic sprint.


FIGURE 58-1 Glycogen synthesis and glycogenolysis. After entering a liver or skeletal muscle cell, glucose is immediately phosphorylated to G6P, which can have three fates: glycolysis, breakdown via the pentose phosphate shunt, imageN58-16 or glycogen synthesis. Glycogenolysis directly yields G1P and is thus not simply the reverse of glycogen synthesis. UDP, uridine diphosphate; UTP, uridine triphosphate.


The Pentose Phosphate Pathway (or Hexose Monophosphate Shunt)

Contributed by Emile Boulpaep, Walter Boron

Figure 58-1 mentions that glucose-6-phosphate can have three major fates. The anabolic series of reactions summarized in this figure convert G6P to glycogen. The glycolytic pathway summarized in Figure 58-6A is a catabolic pathway that converts G6P to pyruvate. The third fate—the pentose phosphate pathway—is another catabolic series of reactions that converts G6P to ribose-5-phosphate.

The pentose phosphate pathway has two major products, NADPH and ribose-5-phosphate. The cell can use the reducing equivalents in NADPH (i.e., energy “currency”) to reduce double bonds in the energy-consuming synthesis of FAs and steroids. These reactions are particularly important in such tissues as liver, adipose tissue, mammary gland, and adrenal cortex. Note that the cell cannot use NADH to create NADPH. Thus, the pentose phosphate pathway is critical. The second product of the pathway, ribose-5-phosphate, is important for the synthesis of ribonucleotides, which is particularly important in growing and regenerating tissues. The pentose phosphate pathway involves four reactions, the first and third of which involve the conversion of NADP+ to NADPH and H+.

If the cell does not use the ribose-5-phosphate to generate ribonucleotides, the cell can use a complex series of reactions to convert the ribose-5-phosphate to fructose-6-phosphate. This sequence of reactions (i.e., from G6P to ribose-5-phosphate to fructose-6-phosphate) bypasses or “shunts” the conversion of G6P to fructose-6-phosphate, which would otherwise be catalyzed by phosphoglucose isomerase (see Fig. 58-6A). For this reason, the pentose phosphate pathway is also called the hexose monophosphate shunt.* However, the reader should be reassured that the shunt does not permit the cell to generate two NADPH molecules for free. Three G6P molecules (3 × 6 = 18 carbons) must traverse the hexose monophosphate shunt to generate six NADPH molecules (3 × 2 = 6) plus two fructose-6-phosphate (2 × 6 = 12 carbons) molecules, a single glyceraldehyde-3-phosphate (1 × 3 = 3 carbons), and three CO2 molecules that arise from a decarboxylation reaction in the pentose phosphate pathway (3 × 1 = 3 carbons). If those three glucose molecules had gone through the classical glycolytic pathway, they would have generated 3 × 2 = 6 net ATPs and 6 NADHs (see Table 58-3). However, if those same three glucose molecules all go through the pentose phosphate pathway, the net result is only five ATPs, only five NADHs, but six NADPHs. Thus, the cell gives up only one ATP and one NADH for the sake of generating six NADPHs—not a bad deal for the cell!


Nelson DL, Cox MM. Lehninger Principles of Biochemistry. 3rd ed. Worth Publishers: New York; 2000.

Voet D, Voet JG. Biochemistry. 2nd ed. Wiley: New York; 1995.

*Note that the term shunt is a bit of a misnomer, inasmuch as the “shunt” is not a shortcut from glucose-6-phosphate to fructose-6-phosphate (normally catalyzed in one step by phosphoglucose isomerase), but rather a lengthy detour!

The liver normally contains 75 to 100 g of glycogen but can store up to 120 g (8% of its weight) as glycogen. Muscle stores glycogen at much lower concentrations (1% to 2% of its weight). However, because of its larger mass, skeletal muscle has the largest store of glycogen in the body (300 to 400 g). imageN58-3 A typical 70-kg human has up to ~700 g of glycogen (~1% of body weight). Thus, the total energy stored in the body in the form of glycogen can be nearly 3000 kcal (Table 58-1); this is still only a tiny fraction of that stored in the form of lipid, enough to supply resting metabolism for less than a day and a half, assuming 100% efficiency. Nonetheless, carbohydrate stores are essential because certain tissues, particularly the brain, rely heavily on carbohydrates for their fuel. Whereas muscle contains the largest store of glycogen in the body, this pool of glycogen cannot contribute directly to blood glucose in response to hypoglycemia because muscles lack glucose-6-phosphatase (G6Pase), which is necessary to convert G6P derived from glycogenolysis to glucose. Instead, the primary role of muscle glycogen is to supply energy locally for muscle contraction during intense exercise.

TABLE 58-1

Energy of Body Stores










9.8/2 = 4.9







*Approximate energy density of hydrated glycogen.

Because only half of this protein can be mobilized as a fuel source, the total yield is only ~21,000 kcal.


Glycogen Supercompensation

Contributed by Kitt Petersen, Gerald Shulman

Exercise induces an increase in GLUT4 expression in skeletal muscle, which leads to an increase in insulin-stimulated glucose uptake and glycogen accumulation. The effect wears off ~40 hours after exercise. Thus, after glycogen has been depleted by exercise, carbohydrate feeding results in enhanced glycogen accumulation, known as supercompensation. Under conditions of supercompensation (i.e., high-carbohydrate feeding following intense exercise), athletes can increase muscle glycogen content to up to 3% of body weight (rather than the usual 1% stated in the text).

If, after intense exercise, supercompensation of rats is prevented by feeding a carbohydrate-poor diet, the increase in GLUT4 expression is substantially prolonged (i.e., 66 versus only 40 hours following exercise).


Garcia-Roves PM, Han D-H, Song Z, et al. Prevention of glycogen supercompensation prolongs the increase in muscle GLUT4 after exercise. Am J Physiol Endocrinol Metab. 2003;285:E729–E736.

Ren J-M, Semenkovich CF, Gulve EA, et al. Exercise induces rapid increases in GLUT4 expression, glucose transport capacity, and insulin-stimulated glycogen storage in muscle. J Biol Chem. 1994;269:14396–14401.

Proteins are linear polymers of L-amino acids (Fig. 58-2), which have the general molecular structure +H3N–HC(R)–COO. Different functional R groups distinguish the 20 amino acids incorporated into nascent proteins during mRNA translation. In addition, four other amino acids are present in mature proteins: γ-carboxyglutamic acid, hydroxylysine, 4-hydroxyproline, and 3-hydroxyproline. However, these amino acids result from post-translational modification of amino acids that are already in the polypeptide chain. In α-amino acids, the amino group (image), the carboxyl group (–COO), and R all attach to the central or α-carbon atom. In proteins, the amino acids are linked together by peptide bonds that join the α-amino group of one amino acid with the α-carboxyl group of another. Nine of the amino acids are termed essential amino acids (Table 58-2) because the body cannot synthesize them at rates sufficient to sustain growth and normal functions. Thus, we must obtain these amino acids in our diet.


FIGURE 58-2 Structure of proteins. The chemistry of R determines the identity of the amino acid.

TABLE 58-2

Essential and Nonessential α-Amino Acids























Proteins contain 4.3 kcal/g, about the same as carbohydrates. A typical 70-kg human with 14% protein (9.8 kg)—only about half of which is available as a fuel source—can thus store ~21,000 kcal (see Table 58-1) in the form of available protein—which could potentially provide ~10 days' worth of energy. Unlike carbohydrate, protein is not a primary energy reserve in humans. Instead, proteins serve other important structural and functional roles. Structural proteins make up skin, collagen, ligaments, and tendons. Functional proteins include enzymes that catalyze reactions, muscle filaments such as myosin and actin, and various hormones. The body constantly breaks down proteins to amino acids, and vice versa, which allows cells to change their protein makeup as demands change. Thus, it is not surprising that protein catabolism makes only a small contribution—much less than 5%—to normal resting energy requirements. In contrast, during starvation, when carbohydrate reserves are exhausted, protein catabolism can contribute as much as 15% of the energy necessary to sustain the resting metabolic requirements by acting as major substrates for gluconeogenesis (see p. 1176).

In the healthy human adult who is eating a weight-maintaining diet, amino acids derived from ingested protein replenish those proteins that have been oxidized in normal daily protein turnover. Once these protein requirements have been met, the body first oxidizes excess protein to CO2 and then converts the remainder to glycogen or triacylglycerols (TAGs).

Lipids are the most concentrated form of energy storage because they represent, on average, 9.4 kcal/g. Lipids are dietary substances that are soluble in organic solvents but not in water and typically occur in the form of TAGs (Fig. 58-3A). The gastrointestinal (GI) tract breaks down ingested TAGs (see pp. 925–927) into fatty acids (FAs) and sn2-monoacylglycerols (see Fig. 58-3B). FAs are composed of long carbon chains (14 to 24 carbon atoms) with a carboxyl terminus, and can be either saturated with hydrogen atoms or unsaturated (i.e., double bonds may connect one or more pairs of carbon atoms). When fully saturated, FAs have the general form CH3–(CH2)n–COOH (see Fig. 58-3C).


FIGURE 58-3 Structures of TAGs and FAs.

In contrast to glycogen and protein, fat is stored in a nonaqueous environment and therefore yields energy very close to its theoretical 9.4 kcal/g of TAGs. This greater efficiency of energy storage provided by fat is crucial for human existence in that it allows for greater mobility and promotes survival during famine. Therefore, although humans have two large storage depots of potential energy (protein and fat), fat serves as the major expendable fuel source. Most of the body's fat depots exist in the subcutaneous adipose tissue layers, although fat also exists to a small extent in muscle and in visceral (deeper) depots in obese individuals. A typical 70-kg human with 20% fat (14 kg) thus carries 131,600 kcal of energy stored in adipose tissue (see Table 58-1). Assuming an RMR of 2100 kcal/day and 100% efficiency of converting the fat to energy, mobilization and subsequent oxidation of this entire depot could theoretically sustain the body's entire resting metabolic requirement for several weeks.