11. The Feed/Fast Cycle

1. 11. The Feed/Fast Cycle

2. Hormonal Regulation of Metabolism • Absorptive state: • Absorption of energy. • 4 hour period after eating. • Increase in insulin secretion. • Postabsorptive state: • Fasting state. • At least 4 hours after the meal. • Increase in glucagon secretion.

3. Absorptive State • Insulin is the major hormone that promotes anabolism in the body. • When blood [insulin] increases: • Promotes cellular uptake of glucose. • Stimulates glycogen storage in the liver and muscles. • Stimulates triglyceride storage in adipose cells. • Promotes cellular uptake of amino acids and synthesis of proteins.

4. Postabsorptive State • Maintains blood glucose concentration. • When blood [glucagon] increased: • Stimulates glycogenolysis in the liver (glucose-6-phosphatase). • Stimulates gluconeogenesis. • Skeletal muscle, heart, liver, and kidneys use fatty acids as major source of fuel (hormone-sensitive lipase). • Stimulates lipolysis and ketogenesis.

5. Effect of Feeding and Fasting on Metabolism Insert fig. 19.10

6. Enzymic Changes in the Fed State • The flow of intermediates through metabolic pathways is controlled by four mechanisms: • the availability of substrates • allosteric regulation of enzymes • covalent modification of enzymes • induction-repression of enzyme synthesis. Each mechanism operates on a different timescale and allows the body to adapt to a wide variety of physiologic situations. In the fed state, these regulatory mechanisms ensure that available nutrients are captured as glycogen, TAG, and protein.

7. 1. Allosteric effects • Allosteric changes usually involve rate-determining reactions. • For example, - glycolysis in the liver is stimulated following a meal by an increase in fructose 2,6-bisphosphate—an allosteric activator of phosphofructokinase-1. Gluconeogenesis is inhibited by fructose 2,6-bisphosphate, an inhibitor of fructose 1,6-bisphosphatase.

8. 2.Regulation of enzymes by covalent modification • Many enzymes are regulated by the addition or removal of phosphate groups from specific serine, threonine, or tyrosine residues of the enzyme. • In the fed state, most of the enzymes regulated by these covalent modifications are in the dephosphorylated form and are active. • Three exceptions are: - glycogen phosphorylasekinase - glycogen phosphorylaseand -hormone-sensitive lipase of adipose tissue, which are inactive in their dephosphorylated state.

9. 3. Induction and repression of enzyme synthesis • - Induction or repression of protein synthesis leads to changes in the total population of active sites, rather than influencing the efficiency of existing enzyme molecules. • Enzymes subject to regulation of synthesis are often those that are needed at only one stage of development or under selected physiologic conditions. • For example, in the fed state: elevated insulin levels result in an increase in the synthesis of key enzymes, such as acetyl coenzyme (CoA) carboxylase and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase involved in anabolic metabolism.

10. Liver: Nutrient Distribution Center • After a meal, the liver is bathed in blood containing absorbed nutrients and elevated levels of insulin secreted by the pancreas. • During the absorptive period, the liver takes up carbohydrates, lipids, and most amino acids. • These nutrients are then metabolized, stored, or routed to other tissues. • Thus, the liver smooths out potentially broad fluctuations in the availability of nutrients for the peripheral tissues.

11. Adipose Tissue: Energy Storage Depot • Adipose tissue is second only to the liver in its ability to distribute fuel molecules. • In a 70 kg man, adipose tissue weighs approximately 11 kg, or about half as much as the total muscle mass. • In obese individuals adipose tissue can constitute up to 70% of body weight. • Nearly the entire volume of each adipocyte can be occupied by a droplet of TAG.

12. Resting Skeletal Muscle • The energy metabolism of skeletal muscle is unique in being able to respond to substantial changes in the demand for ATP that accompanies muscle contraction. • At rest, muscle accounts for approximately 30% of the oxygen consumption of the body, whereas during vigorous exercise, it is responsible for up to 90% of the total oxygen consumption.

13. Heart muscle differs from skeletal muscle in three important ways: 1) the heart is continuously active, whereas skeletal muscle contracts intermittently on demand 2) the heart has a completely aerobic metabolism 3) the heart contains negligible energy stores, such as glycogen or lipid. Thus, any interruption of the vascular supply, for example, as occurs during a myocardial infarction, results in rapid death of the myocardial cells. Heart muscle uses glucose, free fatty acids, and ketone bodies as fuels.

14. Brain • Although contributing only 2% of the adult weight, the brain accounts for a consistent 20% of the basal oxygen consumption of the body at rest. • Because the brain is vital to the proper functioning of all organs of the body, special priority is given to its fuel needs.

15. To provide energy, substrates must be able to cross the endothelial cells that line the blood vessels in the brain (sometimes called the “blood-brain barrier”). • Normally, glucose serves as the primary fuel, because the concentration of ketone bodies in the fed state is too low to serve as an alternate energy source.

16. If blood glucose levels fall below approximately 30 mg/100 ml (normal fasted blood glucose is 70–100 mg/100 ml), cerebral function is impaired. • If the hypoglycemia occurs for even a short time, severe and potentially irreversible brain damage may occur. • Note, however, that ketone bodies play a significant role as a fuel during a fast

17. Fasting • Fasting may result from an inability to obtain food, from the desire to lose weight rapidly, or in clinical situations in which an individual cannot eat, for example, because of trauma, surgery, neoplasm, or burns. • In the absence of food, plasma levels of glucose, amino acids, and TAG fall, triggering a decline in insulin secretion and an increase in glucagon release.

18. The decreased insulin to glucagon ratio, and the decreased availability of circulating substrates, makes the period of nutrient deprivation a catabolic period characterized by degradation of: • TAG, • glycogen, • and protein.

19. This triggers an exchange of substrates between liver, adipose tissue, muscle, and brain that is guided by two priorities: 1) the need to maintain adequate plasma levels of glucose to sustain energy metabolism of the brain, red blood cells, and other glucose-requiring tissues, and 2) the need to mobilize fatty acids from adipose tissue, and the synthesis and release of ketone bodies from the liver, to supply energy to all other tissues.

20. Fuel stores • The metabolic fuels available in a normal 70–kg man at the beginning of a fast are: • 11 – 14 Kg Fat = 135.000 Kcal • 6 Kg protein = 24.000 kcal • 0.2 Kg Glycogen = 800 kcal Note: Although protein is listed as an energy source, each protein also has a function, therefore only about one third of the body's protein can be used for energy production without fatally compromising vital functions.

21. Liver in Fasting • The primary role of liver in energy metabolism during fasting is maintenance of blood glucose through the synthesis and distribution of fuel molecules for use by other organs. • Thus, one speaks of “hepatic metabolism” and “extrahepatic” or “peripheral” metabolism.

22. Adipose Tissue in Fasting • During fasting, the stored TAG in adipose tissue will start undergoing hydrolysis, leading to formation of free fatty acids and glycerol. • Both will enter the blood stream and be used by other tissues.

23. Resting Skeletal Muscle in Fasting • Resting muscle uses fatty acids as its major fuel source. • By contrast, exercising muscle initially uses its glycogen stores as a source of energy. • During intense exercise, glucose 6-phosphate derived from glycogen is converted to lactate by anaerobic glycolysis. • As glycogen reserves are depleted, free fatty acids provided by the mobilization of TAG from adipose tissue become the dominant energy source.

24. Brain in Fasting • During the first days of fasting, the brain continues to use glucose exclusively as a fuel. • Blood glucose is maintained by hepatic gluconeogenesis from glucogenic precursors, such as amino acids from proteolysis and glycerol from lipolysis. • In prolonged fasting (greater than two to three weeks), plasma ketone bodies reach significantly elevated levels, and replace glucose as the primary fuel for the brain. • This reduces the need for protein catabolism for gluconeogenesis. The metabolic changes that occur during fasting ensure that all tissues have an adequate supply of fuel molecules.

25. Kidney in Long-Term Fasting • As fasting continues into early starvation and beyond, the kidneys play important roles. • Kidney expresses the enzymes of gluconeogenesis, including glucose 6-phosphatase, and in late fasting about 50% of gluconeogenesis occurs here. • Kidney also provides compensation for the acidosis that accompanies the increased production of ketone bodies (organic acids).

26. The glutamine released from the muscle's metabolism of branched-chain amino acids is taken up by the kidney and after being converted to α-ketoglutarate, it can enter the krebs cycle. • The resulted ammonia picks up H+ from ketone body dissociation, and is excreted in the urine as NH4+, decreasing the acid load in the body. • In long-term fasting, then, there is a switch from nitrogen disposal in the form of urea to disposal in the form of ammonia.