Medical Physiology, 3rd Edition

Energy Capture (Anabolism)

During feeding, when the energy ingested as food exceeds the energy released by oxidation, the body stores excess calories as glycogen or fat. However, storing energy has a cost, although it is relatively inexpensive from a total-energy standpoint. The process of digesting a mixed meal in the GI tract elevates the whole-body metabolic rate 20% to 25% higher than the RMR for ~90 minutes following a meal. In addition to this cost of digesting and absorbing, the energy cost of storing dietary carbohydrate as glycogen or dietary lipid as TAGs is 3% to 7% of the energy taken in. The cost of storing amino acids as protein is nearly 25% of the energy taken in. Moreover, storage after interconversions among dietary categories is particularly expensive. The cost of storing dietary carbohydrate as TAGs, or of storing amino acids as glycogen, is nearly 25% of the intake energy.

After a carbohydrate meal, the body burns some ingested glucose and incorporates the rest into glycogen or TAGs

Three mechanisms maintain normoglycemia following carbohydrate ingestion: (1) suppression of hepatic glucose production; (2) stimulation of hepatic glucose uptake; and (3) stimulation of glucose uptake by peripheral tissues, predominantly muscle. Insulin is the primary signal, which orchestrates the storage and metabolism of glucose via the insulin receptor (see Fig. 51-5). Glucose is the dominant signal for insulin secretion. However, with meals, other signals converge on the β cells of the pancreatic islets to coordinate insulin secretion, as becomes apparent when one compares the insulin responses to identical amounts of glucose loads given intravenously versus orally (see Fig. 51-3A). Viewed differently, for similar plasma glucose levels, oral glucose raises plasma [insulin] several-fold higher than does intravenous glucose. This differential insulin response is due to the secretion of multiple incretins (see p. 1041)—especially glucagon-like peptide 1 (GLP-1) and gastric inhibitory peptide (GIP)—as well as from parasympathetic innervation of the pancreatic β cells. The incretins and neural signals prime the β cells, magnifying insulin release following meal-induced increases in blood glucose. This priming is absent when blood glucose increases as a result of increased hepatic glycogenolysis in response to stress, and thus minimizes the potentially detrimental hyperinsulinemia during stress.

Liver

Following a carbohydrate meal, levels of insulin and glucose rise in the portal vein (similar to the situation shown in Fig. 51-3A), whereas glucagon levels fall. These changes suppress hepatic glucose production and promote net hepatic glucose uptake. Thus, the liver buffers the entry of glucose from the portal vein into the systemic circulation, thereby minimizing fluctuations in plasma [glucose] while promoting glucose storage. Once plasma [glucose] returns to baseline, the liver resumes net glucose production to maintain normoglycemia. Depending on the size of the carbohydrate load, the liver may take up one fourth to one third of the ingested exogenous glucose load. Because the liver not only decreases its production of glucose but also takes up a significant amount of glucose, the contribution of the liver to postprandial glucose homeostasis is substantial and approaches that of muscle.

Glucose taken up by the liver during the meal is predominantly stored as glycogen. The liver synthesizes glycogen by both a direct pathway from exogenous glucose and an indirect pathway from gluconeogenesis (Fig. 58-8A). When we ingest a meal following an overnight fast, these pathways contribute roughly equally to hepatic glycogen synthesis. However, the relative contributions of these pathways depends on the composition of the diet, the level of glycemia achieved during the meal, and the relative concentrations of insulin and glucagon. A high-carbohydrate diet, hyperglycemia, and insulin promote the direct pathway, whereas reduced carbohydrate intake, lower plasma [glucose], and elevations in circulating [glucagon] stimulate the indirect pathway.

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FIGURE 58-8 Energy storage following meals. A, Three major organs handle the glucose assimilated by the small intestine. Liver stores some glucose as glycogen, and converts some to FAs—packaged as VLDLs—for export to adipocytes. Muscle stores some glucose as glycogen and converts some to lactate and gluconeogenic amino acids for export to the liver. Adipocytes convert glucose to glycerol-3-phosphate, a precursor of TAGs. B, Two major organs handle the amino acids assimilated by the small intestine. Liver converts gluconeogenic amino acids to glycogen. Muscle converts amino acids to glycogen. C, Chylomicrons from the small intestine undergo hydrolysis in systemic blood vessels. Adipocytes re-esterify the resulting FAs (together with glycerol-3-phosphate generated from glucose) for storage as TAGs. ECF, extracellular fluid; RBC, red blood cell.

Hepatic glycogen stores peak 4 to 6 hours following a meal. Thus, when we ingest three meals per day at 4- to 6-hour intervals, hepatic glycogen stores increase throughout the day in a staircase fashion. During this time, most of the glucose required for metabolism comes from exogenous glucose (see dashed arrow in Fig. 58-8A). Glycogen stores reach their peak around midnight, after which hepatic glycogenolysis contributes ~50% to whole-body glucose production and the other 50% derives from hepatic gluconeogenesis.

Because the liver has citrate lyase, it can also convert glucose that it takes up following a meal to FAs (see Fig. 58-8A) via reactions summarized in Figure 58-7. The hepatocyte esterifies these FAs to glycerol to make TAGs, which it packages as VLDLs for export to the blood.

Muscle

Glucose escaping the liver is cleared predominantly by striated muscle, which stores most of this glucose as glycogen (see Fig. 58-8A). Muscle metabolizes the remaining glucose via the glycolytic pathway and then either oxidizes the products or recycles them to the liver, mostly as lactate and alanine.

The uptake of glucose into muscle—as well as adipose tissue—is regulated predominantly by a rise in [insulin] and, to a lesser extent, by the hyperglycemia per se. Insulin, via the phosphatidylinositol 3-kinase (PI3K) pathway (see p. 1042), promotes translocation of the GLUT4 glucose transporter (see p. 1047) to the plasma membrane, and thus stimulates glucose uptake by muscle and fat. In addition, insulin modulates the subsequent metabolism of glucose by increasing the activity of glycogen synthase, thereby promoting glucose storage, and by increasing the activity of pyruvate dehydrogenase, thereby increasing glucose oxidation as well.

Adipose Tissue

Although adipose tissue typically represents a large component of the peripheral mass (10% to 15% of body weight in men, 25% to 30% in women ), adipocytes metabolize only a minor fraction of ingested glucose (see Fig. 58-8C). The reason is that, in contrast to the liver, human adipocytes have a relatively low metabolic rate and contain relatively little citrate lyase, and thus have a low capability of converting glucose into FAs. However, adipocytes use glucose as the starting material for generating glycerol-3-phosphate, imageN58-12 which serves as the backbone for TAG synthesis (see Fig. 58-8A). As we saw above, in times of caloric and carbohydrate excess, the liver (which has an abundance of citrate lyase) synthesizes FAs de novo from glucose and esterifies the FAs to generate TAGs, which it then exports in the form of VLDL particles (see Fig. 46-15). Lipoprotein lipase (LPL; see p. 1050) on the luminal surface of endothelial cells hydrolyzes the TAGs in VLDLs and chylomicrons to FAs. Subsequently the FAs enter adipocytes, which re-esterify them to form TAGs for storage. These adipocytes are mostly in the subcutaneous and visceral tissues and, to a much smaller extent, around muscle.

N58-12

sn-Glycerol-3-Phosphate

Contributed by Kitt Petersen, Gerald Shulman

Glycerol has no asymmetric carbon atoms. However, adding a phosphate group at either end makes the middle carbon atom asymmetric. Depending on whether you assign the appellation carbon 1 to one end of the molecule or the other, the same compound is known either as L-glycerol-3-phosphate or D-glycerol-1-phosphate. Another synonym is α-glycerol phosphate. When stereospecific numbering (sn) is used, the compound is unambiguously known as sn-glycerol-3-phosphate. For the sake of simplicity in the text, we simply refer to it as glycerol-3-phosphate.

The larger the meal, the greater the rate of glucose uptake by liver, muscle, and adipose tissue—because of higher levels of circulating insulin and glucose. In contrast, the brain uses glucose, its major oxidative fuel, at a constant rate, despite these fluctuations in plasma glucose during feeding. GLUT1 facilitates glucose uptake across the blood-brain barrier, and GLUT3 mediates glucose uptake into neurons, independent of insulin (Box 58-1).

Box 58-1

Fructose Ingestion

The hepatic metabolism of fructose differs from that of glucose in ways that are important to human health. Hepatic glucose metabolism is tightly regulated by PFK (see p. 1176), which is inhibited by ATP and citrate. Thus, a sufficient energy status signals hepatocytes to reduce uptake of dietary glucose, much of which now bypasses the liver to reach the systemic circulation. In contrast, dietary fructose is metabolized to fructose-1-phosphate by fructokinase, which is independent of hepatic energy status and the inhibitory effects of high [ATP]i and [citrate]i. Thus, fructose uptake and metabolism by the liver is unregulated, and relatively little ingested fructose reaches the systemic circulation. In the liver, a large fructose load—as from soft drinks sweetened with inexpensive high-fructose corn syrup—can result in increased de novo lipogenesis and inhibition of FA oxidation. This process contributes to the development of hepatic insulin resistance and nonalcoholic fatty liver disease (NAFLD). Owing to the current epidemic of obesity, NAFLD is now the most common liver disorder in adults and children. (Contributed by Fred Suchy.)

After a protein meal, the body burns some ingested amino acids and incorporates the rest into proteins

Following a protein meal, the amino acids absorbed by the GI tract (see pp. 922–925) have two major fates: they can either be oxidized to yield energy or be incorporated into protein. The liver removes a large fraction of amino acids that enter portal blood following a meal, particularly the gluconeogenic amino acids (see Fig. 58-8B). In contrast, the liver less avidly removes the branched-chain amino acids (leucine, isoleucine, and valine), which muscle predominantly captures. Indeed, branched-chain amino acids are critical for the immediate repletion of muscle protein because they have a unique capacity to promote net protein accumulation, predominantly by inhibiting protein breakdown and to some extent by stimulating protein synthesis.

Insulin plays a major role in orchestrating protein anabolism, mostly by suppressing protein degradation. Therefore, the combination of the hyperinsulinemia and hyperaminoacidemia that follows a protein meal not only blocks proteolysis but also stimulates protein synthesis, resulting in net protein accumulation. Because some amino acids (e.g., arginine, leucine) are weak insulin secretagogues (see p. 1139), a protein meal stimulates insulin release even when the meal lacks carbohydrate. Under such conditions, glucagon plays a critical role in preventing potential hypoglycemia by maintaining hepatic glucose production in the face of hyperinsulinemia. In a mixed meal, the presence of carbohydrates augments insulin secretion beyond the effect of protein alone and further enhances protein anabolism.

After a fatty meal, the body burns some ingested FAs and incorporates the rest into TAGs

Following a fat-containing meal (see Fig. 58-8C), lipases in the duodenum hydrolyze the TAGs to FAs and glycerol, which enterocytes in the small intestine take up, re-esterify into TAGs, and secrete as chylomicrons. imageN58-11 The chylomicrons enter the lymphatics and then the systemic circulation.

Insulin, secreted in response to the carbohydrate or protein components of the meal, has three major effects on lipid metabolism. First, insulin induces synthesis of LPL (see p. 1050), which—at the luminal membrane of endothelial cells—promotes hydrolysis of TAGs to FAs and glycerol. The breakdown products enter the adipocytes for re-esterification into TAGs. Insulin promotes storage in muscle and adipose tissue of both exogenous TAGs (derived from a meal and carried in chylomicrons; see p. 930), as shown in Figure 58-8C, and endogenous TAGs (produced by the liver and carried in VLDLs; see p. 968), as shown in Figure 58-8A.

Second, insulin stimulates glucose uptake into adipocytes by stimulating GLUT4. The adipocytes transform the glucose to glycerol-3-phosphate, as discussed above (see p. 1181), which is the backbone required for the re-esterification of FAs into TAGs. Adipocytes lack glycerol kinase and therefore, unlike liver and kidney, are unable to phosphorylate glycerol directly.

Third, in fat cells, insulin inhibits adipose triacylglycerol lipase (ATGL; see p. 1050), which releases an FA from a TAG to form a diacylglycerol (DAG; TAG → DAG + FA), and hormone-sensitive lipase (HSL), which releases an FA from a DAG to form a monoacylglycerol (MAG; DAG → MAG + FA). These enzymes—not to be confused with LPL—catalyze the hydrolysis of stored TAGs in adipocytes. By suppressing lipolysis, insulin markedly decreases plasma [FA] and promotes net storage of absorbed fat into the adipocyte.

In a mixed meal—when glucose, amino acids, and FAs are all available—an increase in plasma [insulin] augments the incorporation of these substances into glycogen, protein, and fat. This is accomplished by inhibiting glycogenolysis, proteolysis, and lipolysis as well as by promoting the opposite of these three processes. Because of the dose-response relationships, low levels of insulin preferentially inhibit the breakdown of energy stores, whereas high levels preferentially stimulate energy accumulation. Thus, small meals (associated with smaller insulin responses) mainly conserve depots by reducing breakdown, whereas larger meals (and concomitant greater insulin responses) increase depots by stimulating storage.