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David L. Nelson and Michael M. Cox Lehninger Principles of Biochemistry Fourth Edition Chapter 23: Hormonal Regulation and Integration of Mammalian Metabolism Copyright © 2004 by W. H. Freeman & Company Chapter Outline • Learn the diverse structures and functions of hormones • Learn how different tissues divide labor • Learn how hormones regulate fuel metabolism • Learn how our body regulate body mass The diverse structures and functions of hormones The way hormone get to their target tissues • Endocrine: blood • Paracrine: diffusion through extracellular space • Autocrine: no Major classes of hormones (p. 886, table 23-1) • • • • • • • • Peptide hormone – glucacon, insulin, TSH Catecholamine - epinephrine Eicosanoids - prostaglandin Steroid - cortisol Calcitriol Retinoid – retinoic acid Thyroid Nitric oxide TSH (thyrotropin-releasing hormone) Insulin are highly concentrated in secretory vesicles Catecholamines are highly concentrated in secretory vesicles http://images.google.com.tw/imgres?imgurl=http://courses.cm.utexas.edu/lmahal/ch310n/fall2005/Epinephrine.png&imgrefurl=http://courses.cm.utexas.edu/lmahal/ch310n/fall2005/MOTD-8.31.05.htm&h=170&w=408&sz=9&hl=zh-TW&start=2&um=1&tbnid=jouiES_HkdmRhM:&tbnh=52&tbnw=125&prev=/images%3Fq%3Depinephrine%26svnum%3D10%26um%3D1%26complete%3D1%26hl%3Dzh-TW%26sa%3DN Eicosanoids are produced when needed Prostaglandin E1 http://content.answers.com/main/content/wp/en/8/8f/Prostaglandin_E1.png They are paracrines. Steroids act through nuclear receptors Vit. D activates an intestinal Ca2+ binding protein http://home.caregroup.org/clinical/altmed/interactions/Images/Nutrients/vitD2.gif RA regulates growth and differentiation by nuclear retinoid receptors http://www.cyberlipid.org/images/pict42.gif Thyroid hormones act through nuclear receptors NO is synthesized from arginine • Arginine + 1½NADPH + 2O2 NO + citrulline + 2H2O +1½NADP+ • This reaction is catalyzed by NO synthase, which is found in many tissues and cell types. How different tissues divide labor Sugar metabolism in Liver Between meals or prolonged fast Glucose-alanine cycle Amino acid metabolism in liver Phospholipids, TG Adipose tissue (bound to serum albumin) Heart & smooth muscle excess Membrane synthesis Citric acid cycle Fatty acid metabolism in liver Adipose tissues • Adipose tissue typically makes up about 15% of the mass of young adult human, with approximately 65% of this mass in the form of triacylglycerols. Adipose tissue glucose pyruvate Acetyl-CoA Fatty acids TAG lipase FA FA epinephrine insulin [ATP] Slow-twitch and Fast-twitch muscle • Slow-twitch (red) muscle: rich in mitochondria, very dense networks of blood vessels; low tension but highly resistant to fatigue • Fast-twitch (white) muscle: fewer mitochondria, less blood vessels; greater tension but quicker to fatigue • The ratio of red/white muscle in any individual is genetically controlled. Muscle 10-30 mM Creatinine kinase reaction Muscleliver cooperation 3 Glycogen G 6-P pyruvate Spend one less ATP Heart muscle • Half of the volume of heart muscle is consisted of mitochondria. • Fuel: free FA, glucose and ketone bodies (blood glucose) gluconeogenesis muscle protein (b-hydroxybutyrate) Brain How hormones regulate fuel metabolism Insulin secretion in pancreas The well-fed state glycogen [Glucose]blood Activate -glycogen phosphorylase -gluconeogenesis (FPBase-1, PEP carboxykinase) Inactivate -glycogen synthase -glycolysis (PFK-1, pyruvate kinase) The fasting state Epinephrine : a stress hormone Cortisol : another stress hormone • Cortisol alters metabolism by changing the kinds and amounts of certain enzymes synthesized in its target cell. • Cortisol restore blood glucose level and increase glycogen stores • Cortisol – Increase adipose tissue fatty acids release from stored TAGs – Increase muscle protein breakdown and export of amino acids – Increase liver gluconeogenesis by stimulating PEP carboxykinase synthesis Diabetes mellitus • Diabetic patients cannot take up glucose efficiently from the blood (GLUT4) • Excessive and incomplete oxidation of fatty acid in the liver • Acetyl-CoA cannot be completely oxidized by citric acid cycle because of high [NADH]/[NAD+] levels, and accumulation of acetyl-CoA leads to overproduction of ketone bodies. Acetone is produced spontaneously by ketone bodies in diabetic patients • The odor of acetone is often mistaken as alcohol. • Ketone bodies will overwhelm the capacity of blood’s bicarbonate buffering system ketoacidosis. Obesity and the regulation of body mass The Lipostat theory • A feedback signal originating in adipose tissue influencs the brain centers that control eating behavior and activity. • Leptin (produced by adipocyte) and leptin receptors (arcuate nucleus of the hypothalamus). Lack of leptin make mice in a constant state of starvation Arcuate nucleus fat-STATs (STATs 3,5,6)