BIOCHEMISTRY - L. Stryer - 1984

VOLUME 2

PART III. BIOSYNTHESIS OF MACROMOLECULAR PRECURSORS

CHAPTER 23. INTEGRATION OF METABOLISM

23.6. Hormonal Regulators of Energy Metabolism

Hormones play a key role in the integration of METABOLISM. In particular, Insulin, Glucagon, epinephrine, and norepinephrine exert a significant effect on the storage and mobilization of energy resources and the metabolic transformations associated with these processes.

Class="center">Fig. 23.17. Electron micrograph of glucagon-containing granules in pancreatic α-Cells

1. Insulin. This is a protein hormone with a Molecular Weight of 5.8 kDa (Secs. 2.6 and 35.8). It is secreted by the β-Cells of the Pancreas and serves as a major regulator of Energy Metabolism. In essence, insulin signals the availability of dietary resources in the body in various ways: it stimulates energy storage and Protein Synthesis. Glycogen synthesis in Muscle and Liver is stimulated by insulin, while Gluconeogenesis in the liver is suppressed. Insulin accelerates Glycolysis in the liver, which in turn enhances fatty acid synthesis. Insulin promotes The entry of glucose into muscle and adipose cells. The Abundance of Fatty acids and glucose in adipose tissue leads to the synthesis and storage of triacylglycerols. The Action of Insulin also extends to the metabolism of Amino Acids and Proteins. Insulin promotes the uptake of branched-chain amino acids (valine, leucine, and isoleucine) by muscle, favoring The formation of muscle protein. Overall, insulin has a stimulating effect on protein synthesis. In addition, it inhibits intracellular protein degradation.

2. Glucagon. This is a polypeptide hormone with a molecular weight of 3.5 kDa (Sec. 16.10). It is secreted by the α-cells of The Pancreas in response to a decrease in Blood glucose concentration. The primary target organ of glucagon is the liver. Glucagon stimulates glycogen breakdown and inhibits its synthesis by triggering a cascade of cAMP-mediated reactions. This results in the phosphorylation of phosphorylase and glycogen synthase (Sec. 16.15). In addition, glucagon inhibits fatty acid synthesis by reducing Pyruvate Formation and acetyl-CoA carboxylase activity. Furthermore, glucagon stimulates gluconeogenesis. Ultimately, all these changes lead to a marked increase in glucose release by the liver. In addition, glucagon increases cyclic AMP levels in adipose cells, which in turn promotes The breakdown of triacylglycerols.

3. Epinephrine and norepinephrine. These hormones are catecholamines. They are secreted by The adrenal medulla and sympathetic nerve endings in response to a decrease in blood glucose concentration. Like glucagon, they stimulate the mobilization of glycogen and triacylglycerols by triggering a cAMP-mediated cascade of reactions. They differ from glucagon in that their glycogenolytic effect is more pronounced in muscle than in the liver. Another function of catecholamines is to inhibit glucose uptake by muscle. Instead of glucose, fatty acids released from adipose tissue are used as an energy source. In addition, epinephrine stimulates glucagon secretion and inhibits insulin secretion. Thus, catecholamines increase The amount of glucose released by the liver into the blood and decrease glucose consumption by muscle.

23.7. The Liver Plays a Buffering Role in the Regulation of Blood Glucose Levels

The normal fasting blood glucose concentration is 80 mg/100 ml (4.4 mM). During the day, blood glucose levels normally fluctuate from 80 mg/100 ml before meals to about 120 mg/100 ml after meals. How is a relatively constant glucose level maintained despite significant variations in its supply and utilization? We have already discussed the main regulatory elements above, so now we will consider them in concert. Blood glucose levels are regulated primarily by the liver, which can absorb and release large amounts of glucose into the blood in response to hormonal signals and to changes in glucose concentration itself (Fig. 23.18). The rise in blood glucose concentration that occurs after a carbohydrate-rich meal, in turn, causes an increase in glucose 6-phosphate levels in the liver, because only under these conditions are the catalytic sites of glucokinase filled with glucose. Recall that glucokinase, unlike hexokinase, has a high K_m for glucose (~ 10 mM, whereas the fasting blood glucose concentration is 4.4 mM) and is not inhibited by glucose 6-phosphate. Consequently, as blood glucose increases, The rate of glucose 6-phosphate formation in the liver increases. The subsequent fate of glucose 6-phosphate is regulated mainly by the opposing actions of glucagon and insulin. Glucagon triggers a cAMP-mediated regulatory cascade (Sec. 16.15), leading to glycogen breakdown, whereas insulin, as an antagonist of glucagon, has the opposite effect. High glucose concentrations lead to decreased glucagon secretion and increased insulin secretion by the pancreas. As a result, when blood glucose levels are elevated, glycogen is rapidly synthesized. These hormonal effects on glycogen synthesis and storage are reinforced by the direct action of glucose itself. As discussed earlier (Sec. 16.18), phosphorylase a, which breaks down glycogen, is sensitive to glucose concentration. When glucose levels are high, the binding of glucose to phosphorylase a makes it susceptible to the action of phosphatase, which converts it to phosphorylase b. Phosphorylase b is unable to break down glycogen. This conversion also releases phosphatase, allowing it to activate glycogen synthase. Thus, glucose allosterically switches Glycogen Metabolism from breakdown to synthesis.

Fig. 23.18. Regulation of Blood glucose levels by the liver. A—after a meal, B—in the morning after fasting

High insulin levels after a meal also promote the entry of glucose into muscle and adipose tissue. Insulin stimulates glycogen synthesis in both muscle and liver. Because of their large mass, Muscles can store about three times as much glycogen as the liver. The entry of glucose into adipose tissue provides glycerol 3-phosphate for triacylglycerol synthesis.

Blood glucose levels begin to decrease several hours after a meal, causing a decrease in insulin secretion and an increase in glucagon secretion. The processes described above then run in reverse. Activation of the cAMP-mediated cascade leads to an increase in the concentration of phosphorylase a and a decrease in the concentration of glycogen synthase a. The Action of Hormones on this cascade mechanism is reinforced by the decreased binding of glucose to phosphorylase a, making it less sensitive to the hydrolytic action of phosphatase. Instead, phosphatase remains bound to phosphorylase a, so that glycogen synthase remains in its inactive phosphorylated form. This achieves rapid glycogen mobilization. The large amount of glucose formed by the Hydrolysis of glucose 6-phosphate after glycogen breakdown is released from the liver into the blood. Reduced glucose consumption by muscle and adipose tissue also contributes to maintaining blood glucose levels. Glucose uptake by muscle and adipose tissue decreases due to low insulin levels. As blood glucose concentration decreases, both muscle and liver use fatty acids as an energy source. Thus, blood glucose concentration is kept above approximately 80 mg/100 ml by three main factors: glycogen mobilization and glucose release by the liver; fatty acid release by adipose tissue; and the switching of muscle and liver to using fatty acids instead of glucose as an energy source.

23.8. Metabolic Adaptation to Prolonged Starvation: Minimizing Protein Degradation

Let us now consider how metabolism adapts to prolonged starvation.

In a normal, non-starving 70-kg adult male, energy reserves normally consist of 1,600 kcal as glycogen, 24,000 kcal as mobilizable protein, and 135,000 kcal as triacylglycerols (Table 23.1). The daily energy requirement ranges from 1,600 kcal at rest to 6,000 kcal depending on the level of activity. Thus, the energy reserve is sufficient to meet the body's needs during starvation for 1 to 3 months. However, the carbohydrate reserve is depleted in just about a day. Despite this, blood glucose concentration is maintained at a level of at least 50 mg/100 ml. The Brain cannot tolerate even a brief drop in glucose concentration below this level. Therefore, the primary task of metabolism during starvation is to ensure a sufficiently high glucose concentration for the brain and other Tissues (such as red Blood Cells) that are completely dependent on this energy source. However, there are not very many glucose precursors in the body. Most of the Energy is stored in the form of fatty acid residues of triacylglycerols. Recall that fatty acids cannot be converted into glucose because acetyl-CoA cannot be converted into pyruvate (Sec. 17.14). The glycerol component of triacylglycerols (triglycerides) can be converted into glucose, but it is available only in limited amounts. This leaves only one potential source of glucose: amino acids derived from protein breakdown. Muscle is the richest source of amino acids during starvation. However, survival for most starving individuals depends on The ability to move, which requires a large muscle mass. Thus, the second task of metabolism during starvation is to preserve proteins. This is achieved by switching metabolism to a pathway in which fatty acids and Ketone Bodies, rather than glucose, are used as Energy Sources (Fig. 23.19).

Fig. 23.19. Concentrations of fatty acids and ketone bodies in blood serum increase during starvation, while glucose concentration decreases

Metabolic changes During the first day of starvation are similar to those in the fasting state after a night's Sleep. Low blood sugar levels lead to decreased insulin secretion and increased glucagon secretion. The dominant metabolic processes are the mobilization of triacylglycerols in adipose tis

sue and gluconeogenesis in the liver. The liver obtains energy for its own needs by oxidizing fatty acids released from adipose tissue. Subsequently, the concentrations of acetyl-CoA and citrate rise, which shuts down glycolysis. Glucose uptake by muscle is significantly reduced due to the low insulin concentration, whereas fatty acids freely enter muscle. Consequently, muscles also switch from using glucose as an energy source to using fatty acids. β-Oxidation of Fatty acids in muscle halts The conversion of pyruvate to acetyl-CoA. As a result, pyruvate, lactate, and Alanine are transported to the liver, where they are converted into glucose. Proteolysis of Muscle Proteins provides some of these three-carbon glucose precursors. Another raw material for glucose synthesis in the liver is glycerol, which is formed during the breakdown of triacylglycerols.

The most important change that occurs after three days of starvation is the formation of large amounts of acetoacetate and β-hydroxybutyrate (ketone bodies) in the liver (Fig. 23.20). Since The Citric Acid Cycle is unable to oxidize all the acetyl groups generated by fatty acid breakdown, the synthesis of ketone bodies from acetyl-CoA increases substantially. Gluconeogenesis depletes the supply of oxaloacetate required for acetyl-CoA to enter The Citric Acid cycle. This leads to The production of large amounts of ketone bodies in the liver, which are released into the blood. By this time, the brain begins to consume significant amounts of acetoacetate instead of glucose. After three days of starvation, about a third of the brain's energy needs are met by ketone bodies (Table 23.2). Heart muscle also uses ketone bodies as an energy source. All of these changes in energy metabolism are referred to as Ketosis.

Fig. 23.20. Ketone Body Synthesis in the liver

After several weeks of starvation, ketone bodies become the primary energy source for the brain (Table 23.2). The brain requires only 40 g of glucose per day, compared to the 120 g it consumes on the first day of starvation. The intensive conversion of fatty acids into ketone bodies in The Liver and their utilization by the brain substantially reduce the demand for glucose. Consequently, muscle protein breakdown decreases compared to the initial days of starvation. Crucial for survival is the breakdown of only 20 g of muscle protein instead of the 75 g at the onset of starvation. The maximum duration of starvation depends on the triacylglycerol stores.

Table 23.2. Energy metabolism during starvation

23.9. Large fat reserves allow migratory birds to cover long distances

Migratory birds provide another striking illustration of the Biological value of triacylglycerols. Some small land birds leave their summer breeding grounds in New England in the autumn to winter in the West Indies, returning in the spring. They fly non-stop over Water for 2400 km. These birds maintain a speed of 40 km/h for 60 h. Such an astonishing feat is made possible by large fat reserves, which are efficiently utilized during the long flight. Birds that migrate short distances or do not migrate at all are relatively lean. Their fat index is approximately 0.3; the fat index is The ratio of the total dry weight of body fat to the fat-free dry body weight of the bird. In contrast, long-distance migratory birds accumulate a significant amount of fat in preparation for their overland journey, and become quite obese just before embarking on their overwater flight. Their fat index reaches 3. The ruby-throated hummingbird accumulates about 0.15 g of triacylglycerols per 1 g of body weight in a single day. In a human, this would correspond to a weight gain of 10 kg per day. The accumulated fat in migratory birds is stored under the Skin, in the Abdominal cavity, in the muscles, and in the liver. During the long overwater flight, about two-thirds of this fat reserve is consumed. The transition to using fatty acids and ketone bodies as an energy source must occur very rapidly, as almost no protein breakdown occurs during the 60-hour flight. Furthermore, fat oxidation provides these birds with the water necessary to compensate for respiratory losses. The high efficiency of Triacylglycerols as a reserve energy source is noteworthy. Recall that triacylglycerols store 6 times more energy than glycogen because they are anhydrous and exist in a more reduced state (Section 17.3). Migratory birds storing the same amount of energy resources as glycogen would never reach land!