Wk1 Ch16.1: Regulation of Organic Metabolism and Energy Balance

• The regular availability is a recent event. Thus mechanisms have evolved for survival during alternating periods of food availability and fasting.
• The 2 functional states the body undergoes in providing energy for cellular activities are:
• The absorptive state: during which ingested nutrients enter the blood from the gastrointestinal tract and
• The postabsorptive state: during which the gastrointestinal tract is empty of nutrients and the body’s own stores must supply energy
• Because an average meal requires approximately 4h for complete absorption, our usual three-meal-a day pattern places us in the postabsorptive state during the late morning, again in the late afternoon, and during most of the night. We will refer to more than 24 h without eating as fasting.

• During the absorptive state, some of the ingested nutrients provide the immediate energy requirements of the body and the remainder is added to the body’s energy stores to be called upon during the next postabsorptive state.
• Total-body energy stores are adequate for the average person to withstand a fast of many weeks, provided water is available.
• A typical meal contains all three of the major energy-supplying food groups—carbohydrates, fats, and proteins—with carbohydrates constituting most of a typical meal’s energy content (calories).
• Carbohydrates and proteins are absorbed primarily as monosaccharides and amino acids, respectively, into the blood leaving the gastrointestinal tract.
• Fat is absorbed into the lymph in chylomicrons, which are too large to enter capillaries. The lymph then drains into the systemic venous system.

• -> will refer to absorbed carbs as glucose for simplicity.
• Glucose is the body’s major energy source during the absorptive state.
• Much of the absorbed glucose enters cells and is catabolized to carbon dioxide and water, in the process releasing energy that is used for ATP formation
• Skeletal muscle makes up the majority of body mass, so it is the major consumer of glucose, even at rest.
• Skeletal muscle not only catabolizes glucose during the absorptive state but also uses some of the glucose to synthesize the polysaccharide glycogen, which is then stored in muscle cells for future use.
• Adipose-tissue cells (adipocytes) also catabolize glucose for energy, but the most important fate of glucose in adipocytes during the absorptive state is its transformation to fat (triglycerides).
• Glucose is the precursor of both glycerol 3-phosphate and fatty acids, and these molecules are then linked together to form triglycerides, which are stored in the cell.
• Another large fraction of the absorbed glucose enters liver cells.
• During the absorptive state, there is net uptake of glucose by the liver. It is either stored there as glycogen, as in skeletal muscle, or transformed to glycerol 3-phosphate and fatty acids, which are then used to synthesize triglycerides, as in adipose tissue.

• Another large fraction of the absorbed glucose enters liver cells.
• During the absorptive state, there is net uptake of glucose by the liver. It is either stored there as glycogen, as in skeletal muscle, or transformed to glycerol 3-phosphate and fatty acids, which are then used to synthesize triglycerides, as in adipose tissue.
• Most of the triglyceride synthesized from glucose in the liver is packaged along with free and esterified cholesterol and coated with amphipathic proteins called apolipoproteins.
• These molecular aggregates of lipids and proteins belong to the general class of particles known as lipoproteins.
• These aggregates are secreted by the liver cells and enter the blood.
• In this case, they are called very-low-density lipoproteins (VLDLs) because they contain much more fat than protein and fat is less dense than protein.
• Because of their large size, VLDLs in the blood do not readily penetrate capillary walls. Instead, their triglycerides are hydrolyzed mainly to monoglycerides (glycerol linked to one fatty acid) and fatty acids by the enzyme lipoprotein lipase.
• This enzyme is located on the blood-facing surface of capillary endothelial cells, especially those in adipose tissue.
• In adipose-tissue capillaries, the fatty acids generated by the action of lipoprotein lipase diffuse from the capillaries into the adipocytes.
• There, they combine with glycerol 3-phosphate, supplied by glucose metabolites, to form triglycerides once again.
• As a result, most of the fatty acids in the VLDL triglycerides originally synthesized from glucose by the liver end up being stored in triglyceride in adipose tissue.
• Some of the monoglycerides formed in the blood by the action of lipoprotein lipase in adipose-tissue capillaries are also taken up by adipocytes, where enzymes can reattach fatty acids to the two available carbon atoms of the monoglyceride and thereby form a triglyceride.
• In addition, some of the monoglycerides travel via the blood to the liver, where they are metabolized.

To summarize, the major fates of glucose during the absorptive state are (1) utilization for energy, (2) storage as glycogen in liver and skeletal muscle, and (3) storage as triglyceride in adipose tissue.

• Many of the absorbed lipids are packaged into chylomicrons that enter the lymph and, from there, the circulation.
• The processing of the triglycerides in chylomicrons in plasma is similar to that just described for VLDLs produced by the liver.
• The fatty acids of plasma chylomicrons are released, mainly within adipose-tissue capillaries, by the action of endothelial lipoprotein lipase.
• The released fatty acids then diffuse into adipocytes and combine with glycerol 3-phosphate, synthesized in the adipocytes from glucose metabolites, to form triglycerides.
• The importance of glucose for triglyceride synthesis in adipocytes cannot be overemphasized. Adipocytes do not have the enzyme required for phosphorylation of glycerol, so glycerol 3-phosphate can be formed in these cells only from glucose metabolites
• There are three major sources of the fatty acids found in adipose-tissue triglyceride:
• (1) glucose that enters adipose tissue and is broken down to provide building blocks for the synthesis of fatty acids;
• (2) glucose that is used in the liver to form VLDL triglycerides, which are transported in the blood and taken up by the adipose tissue; and
• (3) ingested triglycerides transported in the blood in chylomicrons and taken up by adipose tissue (described in this card)
• As we have seen, sources (2) and (3) require the action of lipoprotein lipase to release the fatty acids from the circulating triglycerides.
• Ingested fat is also oxidized during the absorptive state by various organs to provide energy. The relative amounts of carbohydrate and fat used for energy during the absorptive state depend largely on the content of the meal.

• One very important absorbed lipid found in chylomicrons—cholesterol—does not serve as a metabolic energy source but instead is a component of plasma membranes and a precursor for bile salts and steroid hormones.
• Excess cholesterol and high plasma concentrations of cholesterol enhance the development of atherosclerosis, the arterial thickening that may lead to heart attacks, strokes, and other forms of cardiovascular damage.
• Two sources of cholesterol: dietary cholesterol and cholesterol synthesised within the body.
• Dietary cholesterol comes from animal sources, egg yolk being by far the richest in this lipid. Not all ingested cholesterol is absorbed into the blood, however; some simply passes through the length of the gastrointestinal tract and is excreted in the feces.
• Almost all cells can synthesize some of the cholesterol required for their own plasma membranes, but most cannot do so in adequate amounts and depend upon receiving cholesterol from the blood.
• This is also true of the endocrine cells that produce steroid hormones from cholesterol.
• Consequently, most cells remove cholesterol from the blood. In contrast, the liver and small intestine can produce large amounts of cholesterol, most of which enters the blood for use elsewhere.

• First, some plasma cholesterol is taken up by liver cells and secreted into the bile, which carries it to the gallbladder and from there to the lumen of the small intestine.
• Here, it is treated much like ingested cholesterol, some being absorbed back into the blood and the remainder excreted in the feces.
• Second, much of the cholesterol taken up by the liver cells is metabolized into bile salts.
• After their production by the liver, these bile salts, like secreted cholesterol, eventually flow through the bile duct into the small intestine.
• Many of these bile salts are then reclaimed by absorption back into the blood across the epithelium of the distal small intestine

• The liver is clearly the major organ that controls cholesterol homeostasis, for the liver can add newly synthesized cholesterol to the blood and it can remove cholesterol from the blood, secreting it into the bile or metabolizing it to bile salts.
• The single most important response involves cholesterol synthesis.
• The liver’s synthesis of cholesterol is inhibited whenever dietary—and, therefore, plasma—cholesterol is increased. This is because cholesterol inhibits the hepatic enzyme HMG-CoA reductase, which is critical for cholesterol synthesis by the liver.
• Conversely, when dietary cholesterol is reduced and plasma cholesterol decreases, hepatic synthesis is stimulated (released from inhibition). This increased synthesis opposes any further decrease in plasma cholesterol.
• The sensitivity of this negative feedback control of cholesterol synthesis
• differs greatly from person to person, but it is the major reason why, for most people, it is difficult to decrease plasma cholesterol concentration very much by altering only dietary cholesterol.
• A variety of drugs now in common use are also capable of decreasing plasma cholesterol by influencing one or more of the metabolic pathways for cholesterol—for example, inhibiting HMG-CoA reductase—or by interfering with intestinal absorption of bile salts

• Not all plasma cholesterol has the same function or significance for disease.
• Cholesterol circulates in the plasma as part of various lipoprotein complexes. These include chylomicrons, VLDLs, low-density lipoproteins (LDLs), and high-density lipoproteins (HDLs), each distinguished by their relative amounts of fat and protein and the specific nature of their apolipoproteins.
• LDLs are the main cholesterol carriers, and they cholesterol to cells deliver
• throughout the body.
• LDLs bind to plasma membrane receptors specific for the apolipoprotein component of the LDLs and are then taken up by the cells by endocytosis.
• In contrast to LDLs, HDLs remove excess cholesterol from blood and tissue, including the cholesterol-loaded cells of atherosclerotic plaques. They then deliver this cholesterol to the liver, which secretes it into the bile or converts it to bile salts.
• Along with LDLs, HDLs also deliver cholesterol to steroid-producing endocrine cells.

• LDL cholesterol is often designated “bad” cholesterol because a high plasma concentration can be associated with increased deposition of cholesterol in arterial walls and a higher incidence of heart attacks.
• (The designation “bad” should not obscure the fact that LDL cholesterol is essential for supplying cells with the cholesterol they require to synthesize cell membranes and, in the case of the gonads and adrenal glands, steroid hormones.)
• Using the same criteria, HDL cholesterol has been designated “good” cholesterol.
• The best single indicator of the likelihood of developing atherosclerotic disease is the ratio of plasma LDL cholesterol to plasma HDL cholesterol—the lower the ratio, the lower the risk.
• Cigarette smoking, a known risk factor for heart attacks, decreases plasma HDL, whereas weight reduction (in overweight persons) and regular exercise usually increase it.
• Estrogen not only decreases LDL but increases HDL, which explains, in part, why the incidence of coronary artery disease in premenopausal women is lower than in men. After menopause, the cholesterol values and coronary artery disease rates in women not on estrogen-replacement therapy become similar to those in men.
• A variety of disorders of cholesterol metabolism have been identified.
• In familial hypercholesterolemia, for example, LDL receptors are decreased in number or are nonfunctional. 
• Consequently, LDL accumulates in the blood to very high concentrations. If untreated, this disease may result in atherosclerosis and heart disease at unusually young ages.
• Finally, it is becoming clear that LDLs exist in at least two different forms (“a” and “b”) distinguished by their size. The smaller of these forms, LDL-b, appears to be most closely associated with human disease and is now the focus of considerable research.

• Some amino acids are absorbed into liver cells and used to synthesize a variety of proteins, including liver enzymes and plasma proteins
• Or they are used to synthesize carbohydrate-like intermediates known as α-keto acids by removal of the amino group.
• This process is called deamination
• The amino groups are used to synthesize urea in the liver, which enters the blood and is excreted by the kidneys.
• The α-keto acids can enter the Krebs (tricarboxylic acid) cycle and be catabolized to provide energy for the liver cells.
• They can also be used to synthesize fatty acids, thereby participating in fat synthesis by the liver.

• Most ingested amino acids are not taken up by liver cells but instead enter other cells where they are used to synthesize proteins
• All cells require a constant supply of amino acids for protein synthesis and participate in protein metabolism.
• There is a net synthesis of protein during the absorptive state, but this just replaces the proteins catabolized during the postabsorptive state.
• In other words, ingested amino acids in excess of those required to maintain a stable rate of protein turnover are used to synthesize carbohydrate or triglycerides. Therefore, eating large amounts of protein does not in itself cause increases in total body protein.

• Energy is provided primarily by absorbed carbohydrate in a typical meal.
• There is net uptake of glucose by the liver.
• Some carbohydrate is stored as glycogen in liver and muscle, but most carbohydrates and fats in excess of that used for energy are stored as triglyceride in adipose tissue.
• There is some synthesis of body proteins from absorbed amino acids. The remaining amino acids in dietary protein are used for energy or used to synthesize triglycerides.

• As the absorptive state ends, net synthesis of glycogen, triglycerides, and protein ceases and net catabolism of all these substances begins.
• The overall significance of these events can be understood in terms of the essential problem during the postabsorptive state: No glucose is being absorbed from the gastrointestinal tract, yet the plasma glucose concentration must be homeostatically maintained because the central nervous system normally utilizes only glucose for energy.
• If the plasma glucose concentration decreases too much, alterations of neural activity occur, ranging from subtle impairment of mental function to seizures, coma, and even death.
• Like cholesterol, the control of glucose balance is another classic example of the general principle of physiology that homeostasis is essential for health and survival.
• The events that maintain plasma glucose concentration fall into two categories:
• (1) reactions that provide sources of blood glucose; and
• (2) cellular utilization of fat for energy, thereby “sparing” glucose.

• The sources of blood glucose during the postabsorptive state are as follows:
• 1. Glycogenolysis, the hydrolysis of glycogen stores to monomers of glucose 6-phosphate, occurs in the liver.
• Glucose 6-phosphate is then enzymatically converted to glucose, which then enters the blood.
• Hepatic glycogenolysis begins within seconds of an appropriate stimulus, such as sympathetic nervous system activation.
• As a result, it is the first line of defense in maintaining the plasma glucose concentration within a homeostatic range.
• The amount of glucose available from this source, however, can supply the body’s requirements for only several hours before hepatic glycogen is nearly depleted.

• Glycogenolysis also occurs in skeletal muscle, which like the liver contains glycogen.
• Unlike the liver, however, muscle cells lack the enzyme necessary to form
• glucose from the glucose 6-phosphate formed during glycogenolysis; therefore, muscle glycogen is not a source of blood glucose.
• Instead, the glucose 6-phosphate undergoes glycolysis within muscle cells to yield ATP, pyruvate, and lactate.
• The ATP and pyruvate are used directly by the muscle cell.
• Some of the lactate, however, enters the blood, circulates to the liver, and is used to synthesize glucose, which can then leave the liver cells to enter the blood.
• Thus, muscle glycogen contributes to the blood glucose indirectly via the liver’s processing of lactate.

• The catabolism of triglycerides in adipose tissue yields glycerol and fatty acids, a process termed lipolysis.
• The glycerol and fatty acids then enter the blood by diffusion.
• The glycerol reaching the liver is used to synthesize glucose.
• Thus, an important source of glucose during the postabsorptive state is the glycerol released when adiposetissue triglyceride is broken down.

• A few hours into the postabsorptive state, protein becomes another source of blood glucose.
• Large quantities of protein in muscle and other tissues can be catabolized without serious cellular malfunction.
• There are, of course, limits to this process, and continued protein loss during a prolonged fast ultimately means disruption of cell function, sickness, and
• death.
• Before this point is reached, however, protein breakdown can supply large quantities of amino acids. 
• These amino acids enter the blood and are taken up by the liver, where some can be metabolized via the α-keto acid pathway to glucose.
• Synthesis of glucose from such precursors as amino acids, lactate, and glycerol is known as gluconeogenesis—that is, “creation of new glucose.”
• During a 24 h fast, gluconeogenesis provides approximately 180 g of glucose.
• This process is carried out by the liver and kidneys.

• The approximately 180g of glucose per day produced by gluconeogenesis in the liver (and kidneys) during fasting supplies about 720 kcal of energy.
• Typical total energy expenditure for an average adult is 1500 to 3000 kcal/day. Therefore, gluconeogenesis cannot supply all the energy demands of the body during fasting.
• An adjustment must therefore take place during the transition from the absorptive to the postabsorptive state.
• Most organs and tissues, other than those of the nervous system, significantly decrease their glucose catabolism and increase their fat utilization, the latter becoming the major energy source.
• This metabolic adjustment, known as glucose sparing, “spares” the glucose produced by the liver for use by the nervous system.
• The essential step in this adjustment is lipolysis, the catabolism of adipose-tissue triglyceride, which liberates glycerol and fatty acids into the blood.
• We described lipolysis earlier in terms of its importance in providing glycerol to the liver as a substrate for the synthesis of glucose.
• Now, we focus on the liberated fatty acids, which circulate bound to the plasma protein albumin, which acts as a carrier for these hydrophobic molecules.

• Now, we focus on the liberated fatty acids, which circulate bound to the plasma protein albumin, which acts as a carrier for these hydrophobic molecules.
• (Despite this binding to protein, they are known as free fatty acids [FFAs] because they are “free” of their attachment to glycerol.)
• The circulating FFAs are taken up and metabolized by almost all tissues,
• excluding the nervous system.
• They provide energy in two ways
• (1) They first undergo beta oxidation to yield hydrogen atoms (that go on to participate in oxidative phosphorylation) and acetyl CoA, and
• (2) the acetyl CoA enters the Krebs cycle and is catabolized to carbon dioxide and water.

In the special case of the liver, however, most of the acetyl CoA it forms from fatty acids during the postabsorptive state does not enter the Krebs cycle but is processed into three compounds collectively called ketones, or ketone bodies.

• In the special case of the liver, however, most of the acetyl CoA it forms from fatty acids during the postabsorptive state does not enter the Krebs cycle but is processed into three compounds collectively called ketones, or ketone bodies.
• Ketones are released into the blood and provide an important energy source during prolonged fasting for many tissues, including those of the nervous system, capable of oxidizing them via the Krebs cycle.
• One of the ketones is acetone, some of which is exhaled and accounts in part for the distinctive breath odor of individuals undergoing prolonged fasting.
• The net result of fatty acid and ketone utilization during fasting is the provision of energy for the body while at the same time sparing glucose for the brain and nervous system.
• Moreover, as just emphasized, the brain can use ketones for an energy source,
• and it does so increasingly as ketones build up in the blood during the first few days of a fast.
• The survival value of this phenomenon is significant; when the brain decreases its glucose requirement by utilizing ketones, much less protein breakdown is required to supply amino acids for gluconeogenesis. Consequently, the ability to withstand a long fast without serious tissue damage is enhanced.
• The combined effects of glycogenolysis, gluconeogenesis, and the switch to fat utilization are so efficient that, after several days of complete fasting, the plasma glucose concentration is decreased by only a few percentage points. After 1 month, it is decreased by only 25% (although in very thin persons, this happens much sooner).

• Glycogen, fat, and protein syntheses are curtailed, and net breakdown occurs.
• Glucose is formed in the liver both from the glycogen stored there and by gluconeogenesis from blood-borne lactate, pyruvate, glycerol, and amino acids. The kidneys also perform gluconeogenesis during a prolonged fast.
• The glucose produced in the liver (and kidneys) is released into the blood, but its utilization for energy is greatly decreased in muscle and other nonneural tissues.
• Lipolysis releases adipose-tissue fatty acids into the blood, and the oxidation of these fatty acids by most cells and of ketones produced from them by the liver provides most of the body’s energy supply.
• The brain continues to use glucose but also starts using ketones as they build up in the blood.