Energy Metabolism

Energy Metabolism - Chapter 27 Energy Metabolism...

Info iconThis preview shows page 1. Sign up to view the full content.

View Full Document Right Arrow Icon
This is the end of the preview. Sign up to access the rest of the document.

Unformatted text preview: Chapter 27 Energy Metabolism: Integration and Organ Specialization The major energy metabolism pathways Organ specialization Brain • High respiration rate (~20% of the resting O2 consumption) • Most of energy is used for Na+K+ ATPase • Glucose is the primary fuel under usual conditions • During extended fast, ketone bodies are used for the energy production • Requires a constant supply of glucose from the blood – A blood concentration of less than half the normal value of ~5 mM results in brain dysfunction – Levels much below this result in coma, irreversible damage, and ultimate death Muscle • • • • Major fuels are glucose (from glycogen), fatty acids, and ketone bodies Well-fed muscle synthesizes a glycogen store (1 to 2% of its mass) as an energy storage for the faster mobilization Glycogen is converted to glucose-6-phosphate (G6P) for entry into glycolysis Muscle carbohydrate metabolism serves only muscle – No export of glucose – No gluconeogenesis • • • Skeletal muscle uses ~30% of the O2 consumed by the human body Muscle contraction is anaerobic or aerobic The heart is largely aerobic – The heart can metabolize fatty acids, ketone bodies, glucose, pyruvate, and lactate. – Fatty acids are the resting heart’s fuel of choice – During heavy work, it increases the use of glucose derived from a limited glycogen store Source of ATP during exercise in humans Adipose tissue • Storage and release of fatty acids as needed for fuel • Fatty acids for storage are from circulating lipoproteins • In times of metabolic need signaled by a low [glucose] and hormonal stimulation, adipocytes hydrolyze triacylglycerol through the action of lipase – If glycerol-3-phosphate is abundant, the excess fatty acids are reesterified to triacylglycerol – If glycerol-3-phosphate is in short supply, the fatty acids are released into the bloodstream • Adipocytes release an increasing number of hormone, hormone precursors, or cytokines including leptin, resistin and adiponectin Liver • Uptake and release of glucose in response to hormone and to the concentration of glucose itself - glucokinase converts blood glucose to glucose-6-phosphate, the main metabolic intermediate of carbohydrate metabolism • Synthesis and degradation of triacylglycerols • Degradation of amino acids Glucokinase • • • • A liver isozyme of hexokinase Conversion of the excess blood glucose to glucose-6phosphate when [glucose] ~ 6 mM Unlike other hexokinases showing Michaelis-Menten kinetics, glucokinase displays sigmoidal kinetics Depending on the glucose demand, glucose-6phosphate can be converted to glucose, glycogen, acetylCoA (via glycolysis and the action of pyruvate dehydrogenase) or degraded to generate NADPH (via pentose phosphate pathway) Metabolic fate of glucose-6-phosphate in liver Kidney • Filtration of urea and other waste products from the blood • Recovery of important metabolites such as glucose • Maintenance of the blood’s pH – Regeneration of bicarbonate – Excretion of excess H+ as ketone bodies and NH4+ • Gluconeogenesis from α-ketoglutarate (derived from glutamine and glutamate) Interorgan metabolic pathways • The Cori cycle – Lactate produced by muscle glycolysis is transported by the bloodstream to the liver – In the liver, lactate is converted to glucose by gluconeogenesis – The bloodstream carries the glucose back to the muscle • The glucose-alanine cycle – Pyruvate produced by muscle glycolysis is the amino-group acceptor for muscle aminotransferases – The resulting alanine is transported by the bloodstream to the liver – In the liver, alanine is converted back to pyruvate, a substrate for gluconeogenesis – The amino group from the alanine is disposed of via urea synthesis – The bloodstream carries the resulting glucose back to the muscles The Cori cycle The glucose-alanine cycle Hormonal control of fuel metabolism • Hormones from pancreatic islets – Insulin from the β cells (in response to high glucose) – Glucagon from the α cells (in response to low glucose) • Hormones from the adrenal glands – Norepinephrine and epinephrine from the adrenal medulla Pancreatic islet cells Insulin release is triggered by glucose • Glucose enters pancreatic β cells via a passive transporter • Glucokinase converts glucose to G6P, which is exclusively degraded to pyruvate and then converted to acetyl-CoA for oxidation by the citric acid cycle - Direct link between the β cell’s rate of oxidative phosphorylation and the amount of available glucose • Overall level of the β cell’s respitory activity regulates insulin synthesis and secretion Insulin is the primary regulator of blood glucose concentration • • • • • Activation of glucose uptake in muscles and adipose tissue by exocytosis of membraneous vesicles containing GLUT4 Stimulation of glycogen synthase by promoting its dephosphorylation in muscle Activation of the pyruvate dehydrogenase complex and acetyl-CoA carboxylase and increase in the levels of fatty acid synthase in adipocytes Inhibition of hormone-sensitive lipase Inhibition of gluconeogenesis and glycogenolysis in the liver – Decrease in the rate of glycogenolysis by the inactivation of phosphorylase kinase – Increase in the glycogen synthesis by the activation of glycogen synthase – Inhibition of transcription of the genes encoding the gluconeogenic enzymes including phosphenolpyruvate carboxykinase, frucose-1,6-bisphosphatase, and glucose-6-phosphatase – Stimulation of transcrition of the genes for the glycolytic enzymes including glucokinase and pyruvate kinase – Increase in the expression of lipogenic enzymes such as acetyl-CoA carboxylase and fatty acid synthase Glucagon and catecholamines shunt energy reserves to where they are most needed • Glucagon – Activation of glycogenolysis in the liver – the release of glucose to other tissues – Stimulation of fatty acid oxidation by activating hormonesensitive lipase in adipose tissue • Epinephrine and norepinephrine – Activation of the glucagon release from the pancreas – Activation of cAMP- and Ca2+-mediated glycogen breakdown and gluconeogenesis in the liver – Activation of glycogen degradation in muscle – the breakdown of glucose by glycolysis for ATP production – Activation of hormone-sensitive lipase – Stimulation of smooth muscle relaxation in the bronchi and blood vessels supplying skeletal muscle (constriction of the blood vessels supplying skin and other peripheral organs) Hormonal control of fuel metabolism Metabolic homeostasis • The mechanisms that regulate mammalian fuel metabolism permit the body to respond efficiently to changing energy demands and to accommodate changes in the availability of various fuels • Malfunction of such complex system produces acute or chronic diseases including diabetes and obesity Metabolic changes during starvation • • • • • • Blood glucose remains constant in normal condition The body stores less than a day’s supply of carbohydrate After an overnight fast, the increased glucagon and decreased insulin secretion promotes the mobilization of fatty acids from adipose tissue: Muscles switch from glucose to fatty acid metabolism for energy production After a lengthy fast, the rate of gluconeogenesis increases in the liver and kidney In animals, glucose cannot be synthesized from fatty acids – During starvation, glucose is synthesized mainly from amino acids derived from the proteolytic degradation of muscular proteins After several days of starvation, ketone bodies are synthesized from acetyl-CoA in the liver and released into the blood as metabolic fuels, especially for the brain Obesity • • • • A chronic imbalance between fat and carbohydrate consumption and utilization increase the mass of adipose tissue through an increase in the number of adipocytes or their size (once formed, adipocytes are not lost) Obesity has been associated with a large number of life-threatening medical conditions including coronary heart disease, type II diabetes, and sleep apnea The combination of genetic and environmental factors polymorphisms in various genes controlling appetite, metabolism, and adipokine release predispose to obesity, but the condition requires availability of sufficient calories, and possibly other factors, to develop fully An excessive nutrient intake and a sedentary lifestyle are the main cause for the rapid acceleration of obesity in Western society Genetic basis for obesity • Appetite-stimulating peptide hormone – Ghrelin is secreted by the empty stomach • Appetite-suppressing peptide hormones – Leptin, the product of the obese gene, is secreted by adipocytes: “leptin resistance” is associate with obesity – PYY is secreted by the gastrointestinal tract – Insulin Normal (OB/OB) Leptin Knockout (ob/ob) Neurons in the hypothalamus intergrate hormonal signal • NPY/AgRP cells secrete appetite-stimulating hormones – Neuropeptide Y (NPY) – Agouti related peptide (AgRP) • POMC/CART cells secrete appetite-suppressing hormones – α-melanocyte stimulating hormone (α-MSH) – Cocaine and amphetamine-regulated transcript (CART) Hormones that control the appetite Obesity-related peptide hormones Leptin Adipocytes as endocrine cells Diabetes mellitus • • • • • The third leading cause of death in the United States Despite high glucose levels (hyperglycemia), cells starve since insulin-stimulated glucose entry into cells is impaired Triacylglycerol hydrolysis, fatty acid oxidation, gluconeogenesis, and ketone body formation are enhanced Abnormally high ketone body levels (ketoacidosis) are burden on the acid-buffering capacity of the blood and on the kidney Excretion of the excess H+ which is accompanied by the excretion of NH4+, Na+, K+, Pi and H2O causes severe dehydration and decrease in blood volume – ultimately lifethreatening situation Two types of diabetes • Insulin-dependent (type I) diabetes – The deficiency of pancreatic β cells usually results from an autoimmune response – The imprecise metabolic control provided by periodic insulin injection ultimately results in the degenerative complications such as kidney malfunction, nerve impairment, and cardiovascular diseases – Hyperglycemia also leads to blindness through retinal degeneration and the glucosylation of lens proteins, which causes cataracts – A possible treatment would be a β-cell transplant • Non-insulin-dependent (type II) diabetes – Usually occurs in obese individual with a genetic predisposition – Despite normal or elevated insulin levels, target cells are not responsive to insulin (insulin resistance) – A small percentage of cases result from mutations in insulin receptor – The elevated concentration of free fatty acids in the blood caused by obesity could decrease insulin signal transduction – Hyperglycemia and its attendant complications tend to worsen over time – Treated (but not cured) by drugs such as metformin and thiazolidinediones (TZDs) Treatment of type II diabetes • • • • • Metformin decreases glucose release by the liver TZDs increase insulin-simultated glucose disposal in muscle These drugs inhibit Complex I of the mitochondrial electron transport system, leading to the decrease in ATP production and thereby increasing [AMP] The resulting AMPK activity decreases gluconeogenesis in liver and increases glucose utilization in muscle TZDs also decrease insulin resistance by binding to and activating peroxisom proliferator-activated receptor γ (PPAR-γ), which leads to an increase in fatty acid uptake by adipocyte ...
View Full Document

This note was uploaded on 10/16/2010 for the course CHEM 60280 taught by Professor Ryu during the Spring '09 term at TCU.

Ask a homework question - tutors are online