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David L. Nelson and Michael M. Cox LEHNINGER PRINCIPLES OF BIOCHEMISTRY Fifth Edition CHAPTER 23 Hormonal Regulation and Integration of Mammalian Metabolism © 2008 W. H. Freeman and Company In the context of whole organism, hormonal signals integrate and coordinate the metabolic activity of different tissues and optimize allocation of fuels and precursors. The coordination of metabolism is achieved by neuroendocrine system. In neuronal signal, electrical signals (nerve impulses) originate in the cell body of a neuron and travel very rapidly over long distances to the axon tip, where neurotransmitters are released and diffuse to the target cell. The target cell (another neuron, a myocyte, or a secretory cell) is only a fraction of a micrometer or a few micrometers away from the site of neurotransmitter release. In the endocrine system, hormones are secreted into the bloodstream, which carries them throughout the body to target tissues that may be a meter or more away from the secreting cell. Both neurotransmitters and hormones interact with specific receptors on or in their target cells, triggering responses. The structure of thyrotropin-releasing hormone (TRH) Purified (by heroic efforts, 20t hypothalamus from two million sheep) from extracts of hypothalamus, TRH proved to be a derivative of the tripeptide Glu– His–Pro. Hormone act through high specific cellular receptor 1. Hormone and receptor are encounter in extracellular space, cytosol, and nuclei. 2. Six general consequences: 1) A second messenger (cAMP) is generated 2) A receptor Tyr kinase is activated 3) A receptor guanylyl cyclase is activated 4) Change in membrane potential resulted in closing or opening ion-channel 5) Convey information to cytoskeleton 6) Change in gene expression by steroids 3. Water soluble peptide and amine hormone act extracellular through surface receptor. receptor serve as a signal transducer and amplifier. very rapid response : lead to a change in the activity of one or more preexisting enzyme 4. Water insoluble hormone (steroid, retinoid, thyroid) pass through the plasma membrane to reach their receptor proteins in the nucleus. alter gene expresssion slow response Hormone can classified into Endocrine: hormones are release into the blood and carried to target tissue Paracrine: hormones are release into the extracellular space and diffuese to neighboring target cell Autocrine: hormones affect the same cell that releases them. Peptide hormones: 3 to 2000 or more amino acid; insulin, glucagon, and somatostatin; precursor to active form; release by exocytosis; a large amount of hormone release suddenly; bind to receptor; generate second messenger Insulin : preproinsulin (singnal p.p.) proinsulin (secretary vesicle in pancreatic bcell) Insulin Prohormone proteins produce several active hormones. Pro-opiomelanocortin (POMC) Catecolamine hormone: water soluble compound epinephrine and norepinephrine; produced in brain as neurotransmitter and in endocrine hormone in adrenal gland; stored secretary vesicle; exocytosis; bind to receptor; generate second messenger Eicosanoid hormones: not synthesized in advance and stored; produced from arachidonic acid, when they need; most cell produces these hormone and most cell can respond by receptor; paracrine hormone; PG (muscle contraction, pain, inflammation); Tbx (platelet aggregation), LTE (muscle contraction) Steroid hormones: from cholesterol; endocrine; corticosteroid from adrenal cortex; glucocorticoid (metabolism of carbohydrate), mineralocorticoid (regulate the concentration of electrolytes in the blood, androgen(testosterone) from testes and estrogen from ovaries; act through nuclear receptor Vitamin D hormone: carcitriol (Ca2+ homeostasis in blood and bone); produce in liver and kidney; diet or photolysis in skin; acting through nuclear receptor; up-regulation of Ca2+ binding protein in intestine and uptake; bone disease Retinoid hormone: regulate the growth, survival, and differentiation of cells via nuclear retinoid receptor; from b-carotene; in liver; Excess can cause birth defect; pregnant woman are advised not to use the retinoid creams. Thyroid hormone: Tyr residue are enzymatic ally iodinated in the thyroid gland ; act through nuclear receptor; stimulate energy-yielding metabolism by increasing the expression of key metabolic enzyme. Nitric oxid (NO): synthesize from arginine and molecular oxygen by NO synthase; paracrine; entering the target cell and increase cGMP. Hormone release is regulated by a hierarchy of neuronal and hormonal signal 1. The central nervous system receives input from many internal and external sensors and then orchestrates the production of appropriate hormonal signal by endocrine tissues 1) Hypothalamus - coordination center of the endocrine system - it receives and integrates messages from the central nervous system - the hypothalamus produce regulatory hormones (releasing factor) that pass directly to pituitary gland 2) Posterior pituitary gland - axonal endings of many neurons originated from the hypothalamus - these neuron contains short peptide hormones; oxytocine and vasopressin - upon stimulation, hormones in secretory granule are released 3) Anterior pituitary gland - produce tropic hormones or tropins - These peptides activate next level of endocrine glands, such as adrenal cortex, thyroid gland, ovaries, testes The major endocrine glands Cascade of hormone release following central nervous system input to the hypothalamus. 1. In each endocrine tissue along the pathway, a stimulus from the level above is received, amplified, and transduced into the release of the next hormone in the cascade. 2. The cascade is sensitive to regulation at several levels through feedback inhibition by the ultimate hormone (in this case, cortisol). The product therefore regulates its own production, as in feedback inhibition of biosynthetic pathways within a single cell. Specialized metabolic functions of mammalian tissues. The Liver Processes and distributes nutrients 1. The liver has two main cell types - Kupper cells: phagocytes, important in immune function - Hepatocytes: transform dietary nutrients into the fuels and precursors required by other tissues and export them via the blood. 2. Sugars - GLUT2 : glucose transporter of hepatocytes - Glucokinase : high Km for glucose, not inhibited by G-6-P - Phosphorylation of glucose in hepatocyte is minimal, when glucose concentration is low, preventing the liver from consuming glucose as fuel via glycolysis Metabolic pathways for glucose 6-phosphate in the liver 1. 2. 3. 4. 5. Dephosphorylation of G-6-P: replenish blood glucose Glycogen synthesis Pyruvate dehydrogensase reaction: yield energy Incorporate into f.a or cholesterol PPP for yield reducing power , needed for f.a or cholesterol and ribose-5-p, a precursor for nucleotide biosynthesis Metabolism of amino acids in the liver. 1. Produce its own protein: high turnover rate or synthesis plasma protein 2. Pass to other organ to synthesis their own protein 3. Precursors for nucleotides, hormone, other nitrogenouse compounds 4. Degrade into pyruvate and TCA cycle intermedidate; Urea cycle 5. Pyruvate to glucose or glycogen 6. Pyruvate to acetyl Co A 7. Oxidation via TCA cycle 8. Oxidative phosphorylation 9. Convert to lipid 10. Glucose from TAC intermediates 11. Ala from muscle to liver and covert to pyruvate to blood Glc (Glc-Ala cycle) Metabolism of fatty acids in the liver. 1. 2. 3. 4. 5. 6. 7. 8. Convert to liver lipid Act as a primary oxidative fuel in the liver and oxideze to yield to acetylCoA and NADH Further oxidize in TCA cycle ATP generation Ketone bodies Cholesterol, steroid hormones, bile acid Convert to TAGs of plasma lipoprotein Fatty acids are bound to serum albumin and carried to heart and muscle, used as a major fuel Thus liver act as 1) body’s distribution center 2) detoxification 1. 1) 2) 3) White adipocyte Located in under the skin, around deep blood vessel, and the abdominal cavity Filled with single large lipid Metabolically active: glycolysis, TCA cycle, oxdative phosphorylation, synthesis of TAGs (much of TAG is synthesized from liver, transported to adipocyte, stored in adipocytes 4) The release of f.a from adipocyte by epinephrine activate lipolysis 5) Glycerogenesis Brown adipocyte 1. 2. 3. 4. 5. Stored TAG More mitochondria and capillaries Thermogenin, the mitochondrial uncoupling protein thermogenesis In fetus, preadipocyte is differentiated into BAT to generate heat At birth, predipocyte is differentiate in to WAT Energy sources for muscle contraction 1.Muscle is specialized to generate ATP as the immediate source of energy for contraction 2. Two types: Slow-twitch muscle (red muscle) and Fast-twitch muscle (white muscle) 3. Resting muscle: f.a from adipose tissue and ketone bodies from liver Moderately active muscle: f.a + k.b + blood glucose Active muscle: anaerobic fermentation using stored muscle glycogen. Then use phosphocreatine After a period of intense muscular activity, breathing heavily for supply oxygen for oxidativative phosphorylation in liver. The ATP produced is used for gluconeogenesis from lactate and returned to muscle to replenish their glycogen (Cori cycle) 4. Heart muscle: aerobic metabolism; mainly fatty acid as a fuel; small amount of glycogen, lipid, and phosphocreatine, must keep supplying oxygen The brain uses energy for transmission of electrical impulse 1. Adult brain use only Glc as fuel; active respiratory metabolism (use 20% of oxygen), little glycogen, dependent on blood Glc 2. Brain can use b-hydroxybutyrate as fuel in starvation condition. 3. Energy is required to create and maintain an electrical potential across the membrane (Na+K+ ATPase). Blood carries oxygen, metabolite, hormones Role: 1) transport nutrients from small intestine to liver 2) transport waste products from exatrhepatic tissue to liver and to kideny for excretion 3) transport oxygen 4) carries hormonal signal. Hormonal regulation of Fuel metabolism (Insulin) 1. 2. 3. 4. 5. Stimulate Glc uptake by muscle and adipose tissue. Stimulate synthesis of TAG in adipose tissue In liver, activates glycogen synthase and inactivate glycogen phosphorylase. In liver, activate glycolysis and formation of acetyl-CoA. If not further oxidized, acetyl-CoA convert to TAG and transport to adipose tissue In summary, the effect of insulin is to favor to the conversion of excess blood glucose to two storage form, glycogen (in liver and muscle) and TAG ( in adipose tissue) Glucose regulation of insulin secretion by pancreatic b cells. Hormonal regulation of Fuel metabolism (Glucagon) 1. 2. 3. 4. Stimulate the net breakdown of glycogen by activating glycogen phosphorylase and inactivating glycogen synthase. Inhibits glycolysis and stimulate gluconeogenesis. In adipose tissue, activating TAG breakdown free f.a, which exported to the liver and other tissue for fuel. The net effect of glucagon is to stimulate glucose synthesis and release by the liver and to mobilize f.a from adipose tissue, to be used instead of glucose by tissues other than brain. During fasting and starvation, metabolism shifts to provide fuel for the brain 1. 2. Fuel reserve as glycogen (liver), TGA (adipose tissue), and tissue protein Glycogen (in 2 h) TGA (in 4 h) prolong starvation, to provide glucose for the brain 1. 2. 3. 4. Cortisol is released by various stressor ( fear, pain, low blood Glc etc.) Cortisol is relatively slow acting hormone that alters metabolism by changing the amounts and kinds of enzymes F. A release, breakdown muscle protein for gluconeogensis, stimulating the synthesis of PEP carboxykinase The net effect is to restore blood Glc to nomal level and to increase glycogen stores, ready to support the fight or flight response. Obesity and the regulation of body mass The body can deal with an excess of dietary calories in three way:1) convert excess fuel to fat and store it in adipose tissue 2) burn excess fuel by extra exercise 3) waste fuel by diverting it to heat production 1. When the mass of adipose tissue increases (dashed outline), released leptin inhibits feeding and fat synthesis and stimulates oxidation of fatty acids. 2. When the mass of adipose tissue decreases (solid outline), a lowered leptin production favors a greater food intake and less fatty acid oxidation. 1. 2. 3. 4. Adiponectin: a peptide hormone, produced by adipose tissue, increase uptake of fatty acid from the blood by myocyte and rate of b-oxidation in muscle; block fatty acid synthesis and gluconeogenesis Adiponectin triggers activation of AMPK. AMPK shift metabolism from biosynthesis to energy production. AMPK inactivate acetyl-CoA carboxylase. Diet regulates the expression of genes central to maintaining body mass PPARs are transcription factors that, when bound to their cognate ligand (L), form heterodimers with the nuclear receptor RXR. The dimer binds specific regions of DNA known as response elements, stimulating transcription of genes in those regions. Final exam. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 4 problems from mid-term exam without chemical structures Figure 18-10 including chemical structures Figure 18-15 Figure 19-19 Figure 19-29, 29-30, Table 19-5 Figure 19-56 Figure 20-14 Figure 21-6 Figure 23-8 Figure 23-13, Figure 23-14, Figure 23-15 Table 23-3 Table 23-4 Table 23-6 Enzyme cofactors Grade: 70 (mid-term (100) + final (200)) + 30 (attendance + E.P in symposium) Over 90 : A+; 85-90 : A0; 80-85: B+; 70-80: B0; 60-70: C+; below 60: C0