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Transcript
Overview of 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, neoplasms, 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. 5/23/2017 2 • 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. 5/23/2017 3 • This sets into motion 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. 5/23/2017 4 Fuel stores • Enormous caloric stores available in the form of TAG compared followed by glycogen. 5/23/2017 5 Enzymic changes in fasting • In fasting the flow of intermediates through the pathways of energy metabolism is controlled by four mechanisms: • 1) the availability of substrates, • 2) allosteric regulation of enzymes • , 3) covalent modification of enzymes, and • 4) induction-repression of enzyme synthesis. 5/23/2017 6 Liver in Fasting Carbohydrate metabolism • The liver first uses glycogen degradation and then gluconeogenesis to maintain blood glucose levels to sustain energy metabolism of the brain and other glucose-requiring tissues. • The presence of glucose 6-phosphatase in the liver allows the production of free glucose both from glycogenolysis and from gluconeogenesis. 5/23/2017 8 Increased glycogen degradation • During the brief absorptive period, glucose from the diet is the major source of blood glucose. • Several hours after the meal, blood glucose levels have declined sufficiently to cause increased secretion of glucagon and decreased release of insulin. • The increased glucagon to insulin ratio causes a rapid mobilization of liver glycogen stores (which contain about 80 g of glycogen in the well-fed state). • Hepatic glycogenolysis is a transient response to early fasting. 5/23/2017 9 Increased gluconeogenesis • The synthesis of glucose and its subsequent release into the circulation are vital hepatic functions during fasting ②. 5/23/2017 10 Increased gluconeogenesis • Gluconeogenesis, favored by activation of fructose 1,6bisphosphatase (due to a drop in its inhibitor, fructose 2,6bisphosphate) and • by induction of phosphoenolpyruvate (PEP) carboxykinase by glucagon. 5/23/2017 11 Gluconeogenesis • Gluconeogenesis plays an essential role in maintaining blood glucose during both overnight and prolonged fasting. 5/23/2017 12 Fat metabolism Increased fatty acid oxidation: • The oxidation of fatty acids derived from adipose tissue is the major source of energy in hepatic tissue in the postabsorptive state ③. • The fall in malonyl CoA due to phosphorylation (inactivation) of acetyl CoA carboxylase by activated protein kinase (AMPK) removes the brake on carnitine palmitoyl transferase-1 (CPT-1), allowing β-oxidation to occur. • Fatty acid oxidation provides the NADH and the adenosine triphosphate (ATP) required by the liver for gluconeogenesis. 5/23/2017 14 Increased synthesis of ketone bodies • The liver is unique in being able to synthesize and release ketone bodies (primarily 3hydroxybutyrate, (formerly called βhydroxybutyrate) for use as fuels by peripheral tissues (see p. 195). • Note: The liver cannot use ketone bodies as a fuel (lacks thiophorase). 5/23/2017 15 Increased synthesis of ketone bodies • • • • 5/23/2017 Ketogenesis is favored when the concentration of acetyl CoA, produced from fatty acid metabolism, exceeds the oxidative capacity of the TCA cycle. Significant ketogenesis starts during the first days of fasting . The availability of circulating ketone bodies is important in fasting because they can be used for fuel by most tissues, including brain tissue, once their level in the blood is sufficiently high. This reduces the need for gluconeogenesis from amino acid carbon skeletons, thus preserving essential protein. 16 Adipose Tissue in Fasting Carbohydrate metabolism • Glucose transport into the adipocyte and its subsequent metabolism are depressed due to low levels of circulating insulin. This leads to a decrease in fatty acid and TAG synthesis 5/23/2017 18 Fat metabolism • The activation of hormonesensitive lipase and subsequent hydrolysis of stored TAG are enhanced by the elevated catecholamines epinephrine and, particularly, norepinephrine. • These compounds, which are released from the sympathetic nerve endings in adipose tissue, are physiologically important activators of hormone-sensitive lipase ①. • Glucagon also activates the lipase. 5/23/2017 19 Increased release of fatty acids • Fatty acids obtained from hydrolysis of stored TAG are released into the blood ②. • Bound to albumin, they are transported to a variety of tissues for use as fuel. • The glycerol produced following TAG degradation is used as a gluconeogenic precursor by the liver. • Fatty acids are also converted to acetyl CoA, which can enter the TCA cycle, thus producing energy for the adipocyte 5/23/2017 20 Decreased uptake of fatty acids • In fasting, lipoprotein lipase activity of adipose tissue is low. • Consequently, circulating TAG of lipoproteins is not available for TAG synthesis in adipose tissue 5/23/2017 21