Insulin Is a Satiety Hormone

After a hearty meal, the body is flooded with monosaccharides, amino acids, and triglycerides. Not all of this bounty can be oxidized immediately, and excess nutrients have to be stored as glycogen and fat.

Insulin is the hormone of the well-fed state. Its synthesis and release are powerfully stimulated by glucose, and this effect is potentiated by amino acids. Therefore the plasma level of insulin is highest after a carbohydrate-rich meal. The list of insulin effects given in Table 30.1 shows that insulin stimulates the utilization of dietarynutrients, including glucose, amino acids, and triglycerides. It diverts excess nutrients into the synthesis of glycogen, fat, and protein.

Table 30.1 Metabolic Effects of Insulin

* Insulin acts indirectly by promoting the dephosphorylation of phosphofructokinase-2/fructose-2,6-bisphosphatase, thereby increasing the level of fructose-2,6-bisphosphate.

† Insulin acts by promoting the dephosphorylation of the enzyme.

In skeletal muscle and adipose tissue, glucose uptake into the cell through glucose transporter-4 (GLUT4) carriers is the rate-limiting step of glucose metabolism. This step is stimulated 10-fold to 20-fold by insulin.

In the liver, glucose uptake by the insulin-insensitive GLUT2 transporter is not rate limiting, but the glucose-metabolizing enzymes are stimulated by insulin. Insulin induces the synthesis of glycolytic enzymes and represses the synthesis of gluconeogenic enzymes on a time scale of many hours to several days.

On a minute-by-minute time scale, insulin dephosphorylates metabolic and regulatory enzymes, thereby stimulating glycolysis and glycogen synthesis while inhibiting gluconeogenesis and glycogenolysis (see Chapter 22).

Glucose metabolism in brain and erythrocytes is not insulin dependent. These tissues are inept at metabolizing alternative fuels. Therefore they must keep consuming glucose even in the fasting state, when the insulin level is low.

Insulin regulates the metabolism of fat and protein as well as of carbohydrate. It induces the conversion of excess carbohydrate to fat by stimulating glycolysis and fatty acid synthesis. At the same time, it promotes fat synthesis in adipose tissue while inhibiting fat breakdown. Insulin stimulates protein synthesis rather nonselectively, in large part by actions at the level of translation. Thus excess nutrients are used for the synthesis of glycogen, fat, and body protein.

Glucagon Maintains the Blood Glucose Level

The secretion of glucagon from the pancreatic α-cells is increased twofold to threefold by hypoglycemia and reduced to half of the basal release by hyperglycemia. Acting through its second messenger cyclic AMP (cAMP), glucagon up-regulates the blood glucose level when dietary carbohydrate is in short supply. Its actions on the pathways of glucose metabolism are opposite to those of insulin (Table 30.2), but, unlike insulin, glucagon acts almost exclusively on the liver; it has negligible effects on adipose tissue, muscle, and other extrahepatic tissues.

Table 30.2 Metabolic Effects of Glucagon on the Liver*

Catecholamines Mediate the Flight-or-Fight Response

Norepinephrine is the neurotransmitter of postganglionic sympathetic neurons, and both epinephrine and norepinephrine are released from the adrenal medulla in response to acetylcholine released by preganglionic sympathetic neurons. These catecholamines are stress hormones. They are released during physical exertion and cold exposure and also in response to psychological stress (e.g., during a biochemistry examination).

The catecholamines can raise the cellular cAMP level through β-adrenergic receptors, and the calcium level through α₁-adrenergic receptors. Muscle and adipose tissue have mainly β receptors, and the liver has both β and α₁ receptors.

The metabolic actions of the catecholamines are summarized in Table 30.3. These actions, which appear within seconds, are part of the flight-or-fight response. Most important is the mobilization of fat and glycogen reserves for use by the muscles. In muscle tissue itself, the major effects are stimulation of glycogen degradation and glycolysis.

Table 30.3 Metabolic Effects of Norepinephrine and Epinephrine

The regulatory metabolite fructose-2,6-bisphosphate activates phosphofructokinase-1 in muscle, as it does in the liver (see Chapter 22). However, the phosphofructokinase-2/fructose-2,6-bisphosphatase of skeletal muscleis different from the liver enzyme. Its kinase activity is not inhibited but is stimulated by cAMP-induced phosphorylation. Therefore the catecholamines, acting through β receptors and cAMP, stimulate rather than inhibit glycolysis in skeletal muscle.

The catecholamines are functional antagonists of insulin that raise the blood levels of glucose and free fatty acids. They are not very important for blood glucose regulation under ordinary conditions, but their release is potently stimulated by hypoglycemia. Therefore hypoglycemic episodes in metabolic diseases are always accompanied by signs of excessive sympathetic activity, including pallor, sweating, and tachycardia.

Glucocorticoids Are Released in Chronic Stress

Stress, especially chronic stress, stimulates cortisol secretion from the adrenal cortex through corticotropin-releasing factor from the hypothalamus and adrenocorticotropic hormone (ACTH) from the anterior pituitary gland. The metabolic actions of cortisol and other glucocorticoids (Table 30.4) can best be understood as adaptations to life in a dangerous world.

Table 30.4 Important Metabolic Actions of Cortisol and Other Glucocorticoids*

PEP, Phosphoenolpyruvate.

* The glucocorticoid effects are mediated by altered rates of enzyme synthesis.

By and large, the glucocorticoids are synergistic with epinephrine, but there is an important difference. Epinephrine works through the second messengers cAMP and calcium, whereas the glucocorticoids are primarily gene regulators. Therefore epinephrine induces its effects in a matter of seconds, but most glucocorticoid effects are cumulative over many hours to days.

The glucocorticoids prepare the body for the action of epinephrine. They stimulate the synthesis of the hormone-sensitive lipase and the adipose tissue triglyceride lipase. They also increase gluconeogenesis from amino acids by causing net protein breakdown in peripheral tissues and inducing phosphoenolpyruvate (PEP) carboxykinase in the liver. Excess glucose-6-phosphate produced by gluconeogenesis is diverted into glycogen synthesis, thus providing more substrate for epinephrine-induced glycogenolysis.

It now is apparent how cortisol and epinephrine cooperate in a stressful situation. During an extended hunting expedition by a stone-age caveman, cortisol induced the lipases in his adipose tissue and built up the glycogen stores in his liver. As soon as the hunter was attacked by a cave bear, epinephrine immediately stimulated the release of fatty acids from adipose tissue and of glucose from the liver. Thanks to the supply of these fuels to his muscles, the caveman managed to dodge the cave bear’s attack and kill the animal with his club. This gave him the chance to transmit his metabolic regulator genes to us, his descendants.

For the caveman’s degenerate descendants today, the stress hormones are troublemakers rather than lifesavers. Patients suffering from infections, autoimmune diseases, malignancies, injuries, surgery, or psychological upheaval have elevated levels of glucocorticoids and catecholamines. Cortisol-induced protein breakdown leads to negative nitrogen balance and muscle wasting. Because the stress hormones oppose the metabolic effects of insulin, seriously ill patients have insulin resistance and poor glucose tolerance. The insulin requirement of insulin-dependent diabetic patients rises substantially during otherwise harmless infections or other illnesses.

Some cytokines, which are released by white blood cells during infections and some other diseases, have metabolic effects similar to the stress hormones. Interleukin-1 stimulates proteolysis in skeletal muscle, and tumor necrosis factor promotes lipolysis in adipose tissue. These mediators contribute to the weight loss that is common in patients with malignancies or chronic infections.

Energy Must Be Provided Continuously

The basal metabolic rate (BMR) is the amount of energy that a resting person consumes in the “postabsorptive” state, 8 to 12 hours after the last meal. It is calculated with predictive formulas, for example, the Harris-Benedict equation:

In these equations, BMR is calculated as kilocalories per day. Weight is measured in kilograms, height in centimeters, and age in years.

BMR depends on body composition. Men tend to have a higher BMR per body weight than do women because men have relatively more muscle than fat (Table 30.5). Women need more fat as an energy reserve for pregnancy, and men traditionally needed more muscle to fight over the women.

Table 30.5 Metabolic Rates of Various Organs and Tissues

On top of the BMR, additional energy is spent for postprandial thermogenesis (additional energy expenditure after a meal). Postprandial thermogenesis is produced by metabolic interconversions after a meal and by increased futile cycling in metabolic pathways. It depends on the size and composition of the meal. The digestion, absorption, and storage of fat require only 2% to 4% of the fat energy, but the conversion of carbohydrate to storage fat requires 24% of the energy content of the carbohydrate.

Muscular activity is the most variable item in the energy budget but is generally less than 1500 kcal/day except in people who engage in very strenuous physical labor all day long.

Multipliers are used to calculate the caloric expenditure (and dietary requirement) for different physiological states:

Energy is spent round the clock, but most people eat in well-spaced meals. An ample supply is available only for 3 to 4 hours after a typical meal. For the rest of the day, we depend on stored energy reserves that were laid down after meals.

The fat in adipose tissue contains almost 100 times more energy than do the combined glycogen stores of liver and muscle (Table 30.6). Therefore only fat can keep us alive during prolonged fasting. It is easy to calculate that with fat stores of 16 kg and BMR of 1500 kcal/day, people can survive for about 100 days on tap water and vitamin pills alone, actually 125 days if we assume that the metabolic rate in prolonged fasting is 20% below BMR. The time to death on a hunger strike depends on the fat reserves, but survival times near 100 days are typical.

Table 30.6 Energy Reserves of the “Textbook” 70-kg Man

Glycogen is rapidly depleted. It is a checking account from which withdrawals are made on an hour-by-hour basis, whereas fat is a savings account. Indeed, only liver glycogen supplies energy for the whole body. Muscle glycogen is earmarked strictly for muscular activity.

Unlike fat and glycogen, protein is not a specialized energy storage form. Still, much of the protein in muscle and other tissues can be mobilized during fasting. Only the protein in brain, liver, kidneys, and other vital organs is taboo, even during prolonged starvation.

During long-term fasting, net protein breakdown is required to supply amino acids for gluconeogenesis. Because even-chain fatty acids are not substrates of gluconeogenesis, only amino acids are available in sufficient quantity to cover the glucose requirement during fasting. Therefore the loss of protein from muscle and other tissues is inevitable during prolonged fasting.

Figure 30.1 shows some of the changes in blood chemistry during the transition from the well-fed state to starvation. The most important hormonal factor is the balance between insulin and its antagonists, especially glucagon. During fasting, the plasma level of insulin falls, whereas first epinephrine, then glucagon, and finally cortisol levels rise.

Figure 30.1 Plasma levels of hormones and nutrients at different times after the last meal. mM, mmol/liter.

During the first few days on a zero-calorie diet of tap water and vitamin pills, between 70 and 150 g of body protein is lost per day. The rate of protein loss then declines in parallel with the rising use of ketone bodies. Nevertheless, 1 kg of protein is lost within the first 15 days of starvation.

Adding 100 g of glucose to the zero-calorie diet reduces the need for gluconeogenesis and cuts the protein loss by 40%. The addition of 55 g of protein per day to the zero-calorie diet cannot prevent a negative nitrogen balance initially, but many subjects regain nitrogen equilibrium after about 20 days.

Adipose Tissue Is the Most Important Energy Depot

The blood glucose level declines only to a limited extent even during prolonged fasting, but free fatty acid levels rise fourfold to eightfold, and the levels of ketone bodies (β-hydroxybutyrate and acetoacetate) rise up to 100-fold.

Plasma free fatty acids are low after a carbohydrate meal because lipolysis in adipose tissue is inhibited by insulin, and fat synthesis is stimulated. Insulin also stimulates the lipoprotein lipase in adipose tissue but not in muscle after a meal, thus routing the dietary triglycerides in chylomicrons to adipose tissue (Fig. 30.2).

Figure 30.2 Metabolism of adipose tissue after a mixed meal containing all major nutrients and during fasting. A, After a meal. Insulin-stimulated or insulin-inhibited steps are marked by + or −, respectively. B, During fasting. CoA, Coenzyme A, IDL, intermediate-density lipoprotein (VLDL remnant); LPL, lipoprotein lipase; TCA, tricarboxylic acid, VLDL, very-low-density lipoprotein.

During fasting, fat synthesis in adipose tissue is reduced, whereas lipolysis is stimulated by the combination of the low insulin level and the high levels of insulin antagonists. Adipose tissue is very sensitive to insulin, and lipolysis is inhibited even at moderately high insulin levels during the early stages of fasting.

The Liver Converts Dietary Carbohydrates to Glycogen and Fat after a Meal

Being devoid of lipoprotein lipase, the liver is not a major consumer of triglycerides after a meal. It obtains only a small amount of dietary triglyceride from chylomicron remnants. However, the liver metabolizes approximately one third of the dietary glucose after a carbohydrate-rich meal. Because of the high Michaelis constant (K_m) of glucokinase for glucose, hepatic glucose utilization is controlled by substrate availability. Insulin induces the synthesis of glucokinase, but this effect becomes maximal only after 2 or 3 days on a high-carbohydrate diet.

The liver converts at least two thirds of its glucose allotment into glycogen after a meal. Most of the rest is metabolized by glycolysis, but amino acids rather than glucose provide most of the liver’s energy needs after a mixed meal. Much of the acetyl coenzyme A (acetyl-CoA) from glycolysis is channeled into the synthesis of fatty acids and triglycerides. In the liver, glycolysis is the first step in the conversion of carbohydrate to fat. Triglycerides and other lipids from endogenous synthesis in the liver are exported as constituents of very-low-density lipoprotein (VLDL). Insulin coordinates this process by stimulating both glycolysis and fatty acid biosynthesis (Fig. 30.3).

Figure 30.3 Alternative fates of fatty acids in the liver. The regulated steps are as follows: Carnitine acyl transferase-1 is induced in the fasting state. It also is acutely inhibited by malonyl-CoA, the product of the acetyl-CoA carboxylase reaction when fatty acid biosynthesis is stimulated after a carbohydrate-rich meal. Acetyl-CoA carboxylase is induced in the well-fed state. It is inhibited in the fasting state by high levels of acyl-CoA, low levels of citrate (direct allosteric effects), and a high glucagon/insulin ratio (leading to phosphorylation and inactivation). The tricarboxylic acid (TCA) cycle is inhibited when alternative sources supply ATP and NADH. Therefore a high rate of β-oxidation reduces its activity. The ketogenic enzymes are induced during fasting. VLDL, Very-low-density lipoprotein.

The Liver Maintains the Blood Glucose Level during Fasting

In the fasting state, the liver has to feed the glucose-dependent tissues. The brain is the most demanding customer. It is the most aristocratic organ in the body; therefore, it requires a large share of the communally owned resources. Although it accounts for only 2% of the body weight in the adult, it consumes approximately 20% of the total energy in the resting body (see Table 30.5). This large energy demand is covered from glucose under ordinary conditions and from glucose and ketone bodies during prolonged fasting. The brain oxidizes 80 g of glucose per day in the well-fed state and 30 g during long-term fasting.

Three to four hours after a meal, the liver becomes a net producer of glucose. After this time liver glycogen is the major source of blood glucose until 12 to 16 hours after the last meal, when gluconeogenesis becomes the major and finally the only source of glucose. This switch is required because liver glycogen stores are almost completely exhausted after 48 hours. More than half of the glucose produced in gluconeogenesis is from amino acids. Other substrates are glycerol from adipose tissue and lactic acid from erythrocytes and other anaerobic cells (Fig. 30.4).

Figure 30.4 Metabolism of the yoyo dieter’s liver. A, After a meal. Pathways that are stimulated or inhibited by insulin are marked by + or −, respectively. B, Twelve hours after the last meal. C, Four days after the last meal. D, After the first good meal that follows 4 days of fasting. CoA, Coenzyme A; TCA, tricarboxylic acid; VLDL, very-low-density lipoprotein.

Most tissues switch from glucose oxidation to the oxidation of fatty acids and ketone bodies during the transition from the well-fed to the fasting state. Consequently, total body glucose consumption falls (Fig. 30.5). Only tissues that depend on glucose for their energy needs, including brain and red blood cells, do not respond to insulin. They continue to consume glucose even during long-term fasting. The switch from glucose oxidation to fat oxidation leads to a decline of the respiratory quotient (see Chapter 21) from about 0.9 after a mixed meal to slightly above 0.7 in the fasting state.

Figure 30.5 Total body glucose consumption after a meal and during fasting.

Ketone Bodies Provide Lipid-Based Energy during Fasting

The fasting liver spoon-feeds the other tissues with ketone bodies as well as with glucose. In theory, both carbohydrates and fatty acids can be converted into ketone bodies through acetyl-CoA. Actually, however, the liver forms ketone bodies from fatty acids during fasting but not from carbohydrates after a meal.

The liver has only a moderately high capacity for glycolysis, and much of the glycolyzed glucose is converted into fat. Therefore very little is left for ketogenesis. However, the liver has a very high capacity for fatty acid oxidation. Over a wide range of plasma levels, about 30% of incoming fatty acids is extracted and metabolized. This means that hepatic fatty acid utilization is controlled by substrate availability. It rises during fasting, when adipose tissue supplies large amounts of free fatty acids.

The fasting liver has two options for the metabolism of these fatty acids (see Fig. 30.3). One option is esterification into triglycerides and other lipids for export in VLDL, which is released by the liver at all times. The fatty acids of VLDL lipids are made from dietary carbohydrate after a meal but come from adipose tissue during fasting.

The second option is uptake into the mitochondrion followed by β-oxidation. Carnitine-palmitoyltransferase-1, which controls the transport of long-chain fatty acids into the mitochondrion, is induced by glucagon through its second messenger cAMP and by fatty acids through the nuclear fatty acid receptor peroxisome proliferator-activated receptor-α (PPAR-α).

In the well-fed state, carnitine-palmitoyltransferase-1 is inhibited by malonyl-CoA, the product of the acetyl-CoA carboxylase reaction in fatty acid biosynthesis. During fasting, however, acetyl-CoA carboxylase is switched off by high levels of acyl-CoA, low levels of citrate, and a high glucagon/insulin ratio. Malonyl-CoA is no longer formed, and an increased fraction of acyl-CoA can be transported into the mitochondrion for β-oxidation.

The acetyl-CoA that is formed in β-oxidation must be partitioned between the tricarboxylic acid (TCA) cycle and ketogenesis. The activity of the TCA cycle depends on the cell’s need for ATP. It is inhibited by ATP and a high [NADH]/[NAD⁺] ratio (see Chapter 21). β-oxidation produces NADH and, indirectly, ATP. By inhibiting the TCA cycle, these products divert acetyl-CoA from TCA cycle oxidation to ketogenesis.

Ketogenesis amounts to an incomplete oxidation of fatty acids. Whereas the complete oxidation of one molecule of palmitoyl-CoA produces 131 molecules of ATP (see Chapter 23), its conversion to acetoacetate and β-hydroxybutyrate produces 35 and 23 molecules of ATP, respectively. The conversion of 50 g of fatty acids to acetoacetate during a hungry day supplies enough energy to synthesize 190 g of glucose from lactic acid without any need for the TCA cycle.

Why does the liver convert fatty acids to ketone bodies when carbohydrates are in short supply? The main reason is that the brain can oxidize ketone bodies but not fatty acids. Although the brain obtains almost all of its energy from glucose under ordinary conditions, it covers up to two thirds of its energy needs from ketone bodies during prolonged fasting, when ketone body levels are very high. This reduces the need for gluconeogenesis and thereby spares body protein. Liver metabolism in different nutritional states is summarized in Figure 30.4.

The nutrient flows in the body change dramatically in different nutritional states. Figure 30.6 shows the flow of nutrients after different kinds of meal. Figure 30.7 shows the changes during the transition from the well-fed state to prolonged fasting. The intestine provides for all of the body’s needs after a mixed meal, but adipose tissue and liver assume this role during fasting.

Figure 30.6 Disposition of nutrients after different types of meals. A, After a carbohydrate meal (insulin high, glucagon low). B, After a protein meal (insulin moderately high, glucagon high). C, After a fat meal (insulin low, glucagon high). CoA, Coenzyme A; VLDL, very-low-density lipoprotein.

Figure 30.7 Interorgan transfer of nutrients after a mixed meal and during fasting. A, After a mixed meal. B, Postabsorptive state, 12 hours after the last meal. C, One week after the last meal. CoA, Coenzyme A; VLDL, very-low-density lipoprotein.

The refeeding of severely starved patients can be problematic. The levels of glycolytic enzymes in the liver are very low, and patients show profound carbohydrate intolerance. Therefore refeeding should be started slowly, especially in advanced cases.

Obesity Is the Most Common Nutrition-Related Disorder in Affluent Countries

Obesity is the most visible medical problem in modern societies. Its prevalence depends on the definitions used. One convenient measure, the body mass index (BMI), is defined as follows:

BMI of 20 to 24.9 kg/m² is considered normal, BMI between 25 and 29.9 signifies overweight, and BMI of 30 or greater indicates obesity. The prevalence of overweight and obesity in different population groups in the United States during the early 1990s is listed in Table 30.7. The problem has worsened since then. In the United States, 31.1% of adult men and 33.2% of adult women were found to be obese (BMI ≥30) in 2003 and 2004.

Table 30.7 Prevalence of Overweight and Obesity among Adults 20 Years and Older in Different Population Groups in the United States, 2003–2004

Body weight tends to change over the lifespan. In affluent countries, women tend to gain weight between the ages of 20 and 60 years. Men tend to gain weight more slowly from age 20 to age 50 years and to get thinner again after age 60. However, even with constant weight, the amount of lean body mass declines slowly with advancing age whereas fat rises.

Until the early years of the twentieth century, body weight was related to social class, with rich people being heavier than poor people. Socioeconomic status (SES) still is important today, but now poor people are fatter than rich people. A study in the United States found that 30% of low-SES women, 16% of middle-SES women, but only 5% of upper-SES women were obese. A similar but weaker relationship was seen in men.

Actuarial tables of life insurance companies typically show that mortality is lowest in people who are considered 10% underweight. Overweight and obese people, but also those who are severely underweight, are more likely to die. Only among the elderly are slightly overweight people less likely to die than are underweight people, probably because weight loss is an effect (rather than a cause) of aging as well as of many chronic diseases.

By and large, however, obesity is unhealthy. For every 10% rise in relative weight, systolic blood pressure rises by 6.5 mmHg, cholesterol by 12 mg/dl, and fasting blood glucose by 2 mg/dl in men. These associations are only a bit weaker in women. Nevertheless, there is no evidence that weight reduction reduces the mortality of the ex-obese compared to those who remained obese.

Obesity is inevitable when energy intake exceeds energy consumption. After adjustment for age, sex, weight, and lean body mass versus fat, obese people have virtually the same metabolic rate as lean people. This implies that individual variations in appetite control, rather than metabolic rate, are the important cause of obesity. Several rare monogenic forms of obesity are known in humans. Most of them incriminate brain-expressed genes or genes whose products act on the brain. The same seems to be the case for obesity-associated polymorphisms that have been pinpointed in genome-wide association studies.

Appetite is controlled by chemical signals that inform the brain about the nutrient status of the body. High levels of blood glucose, insulin, and fatty acids signal nutrient abundance and suppress appetite. The gastric hormone ghrelin, which is released by the empty but not the filled stomach, stimulates appetite; and the hormone leptin, which is released from adipose tissue when the adipose cells are “filled,” suppresses appetite. Deficiency of either leptin or the leptin receptor causes morbid obesity both in mouse mutants and in some humans.

Normally, the number of adipocytes increases fivefold between the ages of 2 and 22 years. Only 10% of adipocytes are renewed per year during adult life, and a common concern is that overeating, especially at a young age, leads to adipose tissue hyperplasia that is difficult to reverse.

Typically, the metabolic rate of obese people drops by 15% to 20% during weight loss and remains reduced when weight is stabilized at a lower level. Thus the ex-obese have to live permanently with a metabolic rate that is otherwise typical for serious starvation. This is a likely reason why 80% to 85% of weight-reduced obese patients quickly regain until they reach their previous weight. We do not know whether sustained weight reduction for at least a decade leads to a reduced number of adipocytes.

Diabetes Is Caused by Insulin Deficiency or Insulin Resistance

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