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1、According to Robert, the study of endocrinology began in China: isolation of sex (steroid) and pituitary (peptide) hormones from human urine and using them for medicinal purposes 2200 years ago.Many metabolic events might occur in a single cell.Mutually beneficial division of labor among the organs
2、allow each perform functions to serve the short-and long-term interests of the body.Monitors and regulates blood composition;Reduces nutrient fluctuation;Detoxification, etc.High metabolic flexibilityDivision of labor and cooperationamong organs maintain homeostasis in the feeding-fasting cycleBlood
3、Process Center Process Center of metabolismof metabolismATP consumerATP consumer(but contributes(but contributesduring fasting andduring fasting andprolonged starvation)prolonged starvation)ATP consumerATP consumerATP consumerATP consumerStore & supply Store & supply fatty acidsfatty acidsNutrientNu
4、trientabsorptionabsorptionRich in mitochondriaRich in mitochondriaControl center Control center of metabolismof metabolismChanges of plasma concentrations of fatty acids, glucose, and ketone bodies during the first week of starvationnormal (3mM)8Hormones(I exite or arouse): chemical messengers that
5、convey message from one cell to anotherFunction in small amount and to be activated(secreted) by a particular stimulus;Involves a hierarchical signal amplification & triggers a cascade of secondary effects ;Different tissues often respond differently to the same hormone; Often form negative feedback
6、 loops to maintain the homeostatic status. Effective concentration of hormone-receptor complexesdetermines signaling initiation. Three major types: peptides; lipids, monoaminesErnest Starling(1905 on secretin)(William BaylissThe homeostatic negative (or positive) feedback loops not shown here!Coordi
7、nation Center Hypothalamus controls body temperature, hunger, thirst,fatigue, sleep, and circadian cycles. Master endocrine glandSecondary endocrine glandsTarget tissuesNeronal connectionsThe hierarchy of hormonal The hierarchy of hormonal signaling starts from the CNS and signaling starts from the
8、CNS and integrate metabolism of different integrate metabolism of different organs to achieve homeostasis organs to achieve homeostasis in the bodyin the body. . Guillemin, Schally(Nobel, 1977)All hormones secreted by the pituitary gland are peptide hormones!Hormonal cascades Coordination Center Mas
9、ter endocrine glandSecondary endocrine glandTarget tissues41 amino acid s39 Amino acidsFeedback inhibitionA radioimmunoassay (RIA) was developed to measure extremely low concentrations of peptide hormones by use of antibodies (1960, Yalow)(measured before based on the biological effect they generate
10、 in animals, thus very unreliable)Rosalyn Yalow(1921- Shared 1977 Nobel Prize in Physiology or Medicine Cold antigen competes with the hot antigens in binding to the antibodies. (1012 g)1012 gNoble Prize, 1977(Known quantity)(Known quantity)(Unknown quantity)The standard curveYalow RS, Berson SA (19
11、60). Immunoassay of endogenous plasma insulin in man. J. Clin. Invest. 39: 115775.Precise measurement of minute amounts of peptide hormones revolutionized the field of endocrinology!Separating bound from unbound antigen is crucialThe insulin A and B chains proposed to be madeas a single polypeptide
12、chain and confirmed inhuman islet cell adenoma (1967) High molecular weight immunoreactive ACTH (1971); Immunoprecipitation byantibodies of multiple hormones (1978); Isolation cDNA cloning (1979)In pituitary (285 residues) 44 residues Insulin stimulates glucose uptake and Insulin stimulates glucose
13、uptake and storage in liver, muscle and adipose cells.storage in liver, muscle and adipose cells.The well-fed state:The well-fed state:Stored as glycogenStored as glycogenor triacyglycerol.or triacyglycerol.Secretion stimulated by an increase in blood glucose level. b b cellsFrederick Banting John M
14、acleod Nobel prize, 1923Charles Best James Collip Insulin binds to its receptor (1), which starts many protein activation cascades (2) leading to: Translocation of Glut-4 to plasma membrane; Influx of glucose (3), Glycogen synthesis (4), Glycolysis (5) Fatty acid synthesis (6). Well-fed stateGlucago
15、n stimulates glucose production and release in liver.The fasting state:Also mobilizes the fatty acids(sparing glucose for the brain)a a cells29-residue peptideGPCRDiscovered as an additional substancein insulin preparation of pancreatic extracts that raised blood sugar (hyperglycemic, intead of hypo
16、glycemic) in depancreatized dogs. (Kimball and Murlin, 1923)A monoamine derived from TyrGPCRJeffrey M. Friedman Genes cloned (1994) from Genes cloned (1994) from massively obese homozygous homozygous “obob/ /obob ” mice mice (reported in 1950).(reported in 1950).Zhang Y, Proenca R, Maffei M, Barone
17、M, Leopold L, Friedman JM (1994). Positional cloning of the mouse obese gene and its human homologue. Nature 372 : 425432.“ob/ob ” “ob/ob ”(4 X weighter) Leptin(1994)A set-point modelfor maintaining a constant body massLeptin:a “satiety hormone” produced in direct proportion to fat mass (adipocytes)
18、Other satiety hormones - cholecystokinin, nesfatin-1, obestatin. hunger hormones - ghrelin, orexin, and PYY 3-36. Neurosecretory cellsHormones andneuropeptidecontrol eating behaviorsHypothalamusAppetite-inhibiting Appetite-stimulating But the leptin level in obese animals are usually higher than normal animals! So much needs to be learned about the action of leptin. 28-amino acid hunger hormoneGood luck for the final Good luck for the final exam!exam!
生物化學(xué)：chapter 23 Integration and Hormonal regulation of mammalian metablism
