Chapter 38?Hormonal Regulation of Energy Metabolism Overview of Energy Metabolism Adenosine Triphosphate Forms of energy expenditure involve: Thermogenesis induced by diet or to maintain constant body temp Fidgeting and purposeful exercise (including labor) BMR accounts for 60-70%, thermogenesis for 5-15%, and physical activity for 20-30% of average daily expenditure Cells derive energy to perform this work from ATP Not stored but continuously made?mainly from oxidizing glucose, free fatty acids, amino acids, and ketone bodies Ketone bodies are made by the liver for use by other organs during fasting 40% efficient, with other 60% leaving as heat Fuel comes from the diet Metabolic Phases Digestive/absorptive Interdigestive/postabsorptive Fasting Strenuous exercise Brain accounts for 20% of O2 consumption Converts most of its AA pool into neurotransmitters instead of oxidizing them for energy Brain function is almost entirely dependent on glucose levels Cells with no or very few mitochondria (like the brain) cannot utilize AAs and FFAs for energy but must rely entirely on anaerobic glycolysis Hypoglycemia leads to impaired NS functions as well as lethargy and weakness All organs and tissues cannot simply transport glucose from blood and oxidize it to the same extent at all times ATP Synthesis Making ATP from Carbohydrates Primary carbohydrate for ATP synthesis is glucose?three main phases involved: Transport and trapping of glucose inside cell Once inside, its prevented from leaving by phosphorylation to a bigger molecule Glycolysis Yields a net production of 2 moles of ATP and pyruvate TCA cycle (referred to as citric acid in her awful notes), which occurs in the inner mitochondrial matrix in close proximity to components of the electron transport chain, and oxidative phosphorylation Pyruvate enters mitochondria and is converted to acetyl CoA Acetyl CoA is then further metabolized in the TCA cycle and the closely coupled process of oxidative phosphorylation via electron transport chain Oxidative phosphorylation can only proceed as fast as respiratory and CV systems can deliver O2 to tissues ATP can also be made from Free Fatty Acids, Amino Acids, and Ketone Bodies Storage Forms of Energy Glycogen Large polymer of glucose molecules Broken down during postabsorptive period Triglyceride Storage form of nutrient lipid (like FFAs) Can be stored in most tissues, but only adipose tissue is a safe and efficient storage depot Can be converted into lipoprotein particles called chylomicrons for transport through the blood HDL (good cholesterol) and LDL (bad cholesterol) Catabolism of Triglycerides in Adipose Cells Done during fasting period Protein Metabolically active and can be hydrolyzed to produce AAs (next comes oxidation or gluconeogenesis) Synthesis reduced during fasting conditions Gluconeogenesis: Synthesizing Glucose from Glycerol, Lactate, and Amino Acids Can be used instead of converting glycogen to glucose (liver) Done by the liver and, to a lesser extent, the kidneys Mechanism is fucking difficult?not needed Involves (pyruvateoxaloacetatemalate or phosphoenolpyruvate [PEP]) PEP subsequently converted to fructose-1,6-biphosphate then G6P Acetyl CoA cannot be used to make glucose Summary of Key Metabolic Pathways ATP primary source of cells? energy Synthesized from carbohydrates, FFAs, AAs, and ketone bodies Brain is exclusively dependant on glucose except after days of fasting, after which it can metabolize ketone bodies Excess calories are stored as glycogen, TGs, and protein during a meal Stored energy substrates are released during fasting and/or physical activity Key Hormones Involved in Metabolic Homeostasis Endocrine Pancreatic Hormones Islets of Langerhans constitute the endocrine portion of the pancreas; make mad cells Most abundant cell type produced is the beta cell (B cell) Make up 75% of islets? cells and produce insulin Alpha cells (A cells) constitute 10% of islets? cells and produce glucagon Blood flow goes from the center of the islet to the peripheral A cells in periphery and B cells in center; A cells are the first ones affected by circulating insulin Insulin Primary anabolic hormone responsible for maintaining upper limit of blood glucose and FFA levels. Promotes glucose uptake and utilization by muscle and adipose tissue, which increases glycogen storage in the liver and muscle, and reduces glucose output by liver Promotes protein synthesis from AAs and inhibits protein degradation in peripheral tissues Promotes TG synthesis in the liver and adipose tissue and represses lipolysis of adipose TG stores Regulates metabolic homeostasis through effects on satiety Glucose is the Primary Stimulus of Insulin Secretion Entry of glucose into B cells facilitated by GLUT2 transporter Metabolized via glucokinase into G6P Increases intracellular ATP/ADP ratio and closes an ATP-sensitive K+ channel Results in depolarization of B cell membrane, which opens voltage-gated Ca++ channels Increased intracellular [Ca] activates exocytosis of insulin/proinsulin-containing secretory granules Diabetes! Glucagon Primary counterregulatory hormone that increases blood glucose levels through its effects on liver glucose output Promotes glucose production via glycogenolysis and gluconeogenesis (elevated and decreased) Epinephrine and norepinephine increase intracellular cAMP and initiate sympathetic response (thanks to hypothalamic neuron signaling) to decreased glucose concentrations Metabolic Homeostasis: The Integrated Outcome of Hormonal and Substrate/Product Regulation of Metabolic Pathways Blood glucose levels determined by the absorption of food and flow of recently absorbed or stored energy substrates through different metabolic pathways Key enzymatic reactions determine relative flow of carbon through different pathways Enzymes regulated by substrate and product concentrations Also by endocrine and autonomic regulation of enzyme gene expression and/or activity Fasting-to-Fed State Transition Involving Anabolic Pathways that Store Energy Ingestion of a meal stimulates B cells to release insulin This inhibits A cells? glucagon secretion Increased insulin-glucagon ratio causes liver to increase hepatic glucose utilization High ratio also inhibits hepatic glucose-producing pathways Glycogenolysis and gluconeogenesis Once glycogen stores are saturated (up to 100g), excess glucose used to make TGs Fatty acyl CoA synthesis mentioned?not needed? Insulin in the liver regulates: Trapping intracellular glucose Increasing glycogen synthesis Increasing glycolysis Increasing synthesis of TG (triglyceride) Insulin in the liver indirectly inhibits oxidation of FFAs by activating steps that lead to the generation of malonyl CoA Ultilization of Glucose by Skeletal Muscle and Adipose Tissue Glucose tolerance refers to ability of a person to minimize increase in [blood glucose] after a meal Promoted by insulin Activation of glucose transporters in skeletal muscle Amount of glucose used for energy is dependent on person?s lifestyle Insulin promotes release of FFAs from chylomicrons in adipose tissue Could later be converted into TGs Insulin promotes protein synthesis in muscle and adipose tissue by stimulating AA uptake and mRNA translation Release of Energy During the Interdigestive Period or an Extended Fast Liver and a High Glucagon-Insulin Ratio during a Fast Nutrient levels in blood fall several hours after a meal Lower levels of insulin secretion This relieves inhibition of glucagon secretion Effects of this on hepatic metabolism: Glycogen phosphorylase activated, while the antagonist enzyme is inhibited through phosphorylation Gluconeogenic enzymes increased?gluconeogenesis takes over as primary pathway of hepatic glucose production Supports blood glucose levels days during extended fast Lipogenesis inhibited Ketogenesis supplements blood glucose a while later for brain purposes Hepatic Metabolism Substrates available for gluconeogenesis (that the liver NEEDS) originate from skeletal muscle and adipose tissue Lactate, AAs, and glycerol Glucagon mostly inactivated by liver No glucagon receptors in muscle; has small effect on adipose tissue Adrenaline and noradrenaline released to respond to chronic hypoglycemia through ANS mechanism During fasting, both skeletal muscle and adipose tissue contribute directly to circulating blood glucose through release of gluconeogenic substrates and indirectly through release of FFAs Release of FFAs and ketogenic AAs supports ketogenesis by the liver Release of Energy During Exercise Intense, short-term exercise Stored creatine phosphate and ATP provide the energy at a rate of about 50kcal/min When these are depleted, additional intense exercise for up to 2 minutes can be sustained by breakdown of muscle glycogen to G6P Accumulation of lactid acid After several minutes of anaerobic exercise, an O2 debt of 10-12 L must be repaid before repetition of the exercise 6-8 L of O2 needed to break down lactic acid into glucose in liver or oxidize it to CO2 2 L of O2 needed to replenish muscle ATP and creatine phosphate stores Final 2 L needed to replenish normally present O2 in lungs, body fluids, and myo/hemoglobin Less intense but longer periods of exercise Aerobic oxidation of substrates is required to produce the necessary energy of about 12 kcal/min Uptake of glucose from plasma increases up to 30X in some muscle groups During exercise, intracellular glucose and ATP levels initially fall while AMP levels rise To offset this drain, hepatic glucose production increases up to 5X Via Glycogenolysis This is how increased carb intake days before a marathon is helpful Longer duration exercise requires gluconeogenesis Fatty acids from TGs in adipose tissue also supply energy?about 2/3 of the needs during sustained exercise Leptin and Adipose Tissue Adipose is spread throughout the body Brown Adipose Tissue and White Adipose Tissue BAT for newborns; WAT for storage in adults Leptin is an adipocyte (TG-storing cell)-derived protein that signals information to the hypothalamus about the degree of adiposity and nutrition Represses production of neuropeptide Y (NPY), which stimulates food-seeking behavior Controls eating behavior and energy expenditure If you?re leptin-less you?re going to become morbidly fat Fat people have developed leptin resistance Enhances erythropoiesis, lymphopoiesis, and myelopoiesis 25% of variance in total body fat appears to be genetic BMI Healthy BMI: 20-25 BMI>30=obese Liver clears intraabdominally derived FFAs Muscle uses subcutaneous fat FFAs Men usually gain fat around abdomen (beer bellies) while women tend to gain fat mostly around thighs and butt Waist circumference / hip circumference Ratio may be a better indicator of body fat than BMI >.95 in men or >.85 in women linked to a significantly higher risk for development of diabetes and CV disease Ghrelin indicates hunger Plasma levels rise 1-2 hours before a meal, and fall to min. values an hour after a meal
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