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Transcript
Endocrine Glands and the General Principles of Hormone Action Cai Li, Ph.D. Assistant professor Touchstone Center for Diabetes Research Departments of Physiology and Internal Medicine The University of Texas Southwestern Medical Center Dallas, TX 75390-8854 April 6, 2002 “Classical” Endocrine Glands A more complete listing of the endocrine glands Endocrine gland Major hormones Adipose tissue Adrenal cortex Leptin Glucocorticoids Aldosterone Epinephrine Atrial natriuretic hormones Releasing and inhibiting hormones Secretin, cholecystokinin Insulin glucagon erythropoietin Somatomedins estradiol, progesterone Parathyroid hormone Melatonin Trophic hormones Antidiuretic hormone oxytocin 1,25-dihydroxy vitamin D3 Gastrin Testosterone Thymosin T3, T4, calcitonin Adrenal medulla Heart Hypothalamus Small intestine Islets of Langerhans Kidneys Liver Ovaries Parathyroid glands Pineal gland Pituitary, anterior Pituitary,posterior Skin Stomach Testes Thymus Throid gland Primary target organs hypothalamus liver, muscle kidneys heart, blood vessels kidneys pituitary stomach, liver, pancreas fat, muscle, brain liver, fat bone marrow cartilage repro. tract, mammary glands bone, small intestine, kidneys hypothalamus, ant. Pituitary endocrine glands kidney, blood vessels uterus, mammary glands small intestine Stomach prostate, seminal vesicles lymph nodes Many Exocrine and Endocrine Glands Exocrine Glands and Endocrine glands Exocrine Glands: Examples: Endocrine Glands: Examples: Secrete into a duct and to the outside of a body surface sweat, tear, saliva Secrete (hormone) into the blood Hormone circulates in blood and acts at target organs where hormone receptor is expressed insulin Exocrine and Endocrine glands: Liver: Pancreas Endocrine IGF Pancreatic juice Exocrine Bile insulin, glucagon, PP Chemical Structure of Hormones 1. Amines (amino acid derivatives) Tyrosine derived: epinephrine, thyroid hormones Tryptophan derived: melatonin 2. Polypeptides Insulin, leptin, ADH 3. Glycoproteins FSH, LH 4. Steroids (cholesterol derived) Glucocorticoids, testosterone, vitamine D Mechanisms of Actions of Hormones All hormones act by binding to their receptors • Some receptors are located on the cell surface Polar hormones (insulin, leptin) • Some receptors are located in the cytoplasm Lipophilic hormones (steroids, thyroid hormones) • Some receptors are located in the nucleus Lipophilic hormones (TZDs, Fibrates) Assay and Measurement of Hormones % *Hormone bound Bioassay Chemical assay Radioimmunoassay (1977 Nobel prize) # [hormone] (ng/ml) Receptor binding assay (Scatchard plot) Action of nuclear hormones Actions of PPARγ, a nuclear hormone receptor Regulation of hormone secretion: A simple feedback loop ↑ Blood glucose ↓ β cells in the pancreas ↓ ↑ Insulin secretion ↓ ↑Uptake of blood glucose Liver Muscle Glucose ↓ Glycogen Fat Glucose ↓ Triglyceride ↓ blood glucose Structure of an islet How glucose and therapeutic drugs cause insulin secretion Two general principles of hormone action Acts on cells containing the receptor Action is regulated by a feedback mechanism Overweight and NIDDM 60% 180 _ Millions of People in the U.S. 54% 150 _ 120 _ 33% 90 _ 60 _ ? 28% 30 _ 0 1980 1990 2000 2010 Leptin: a new hormone from fat •Made in the adipose tissues •A polypeptide of 167 amino acids •Product is secreted into blood •Its receptor is found in many tissues •Leptin deficiency causes obesity, infertility, and many other •complications Tissue distribution of leptin Leptin gene mutation in ob/ob mouse R105 (CGA→TGA) ob/ob R105 (CGA→TGA) 167 Leptin Receptor Isoforms Extracellular TMR Intracellular Long OB-Rb 1162 Short OB-Ra 894 OB-Rc 892 OB-Rd Soluble OB-Re 900 805 Kidney Testis Sk. Muscle Liver Lung Spleen Brain Heart Tissue distribution of the leptin receptor Probe Length (kb) Common 0.60 Ob-Ra 0.25 Ob-Rb 0.20 Actin 2.00 Rodent Mutations at the db Locus Mouse Extracellular TMR Intracellular Ob-Rb 1162 C57BL/KsJ db/db 894 db3J/db3J dbPas/dbPas Rat 625 281 Q269P fa/fa fak/fak 1162 762 Leptin Levels in Lean and Obese Rodents +/+ db/db +/+ fa/fa Leptin western Leptin northern β-actin Leptin levels in lean and ZDF rats 14 Leptin (ng) 12 10 8 6 4 2 0 Plasma (µl) 1 2 5 10 ZDF 25 50 50 Lean Soluble Leptin Receptor Levels in Lean and ZDF Rats Lean M.W. (kDa) Plasma (µl) 100 ZDF 1 2 5 10 20 203 116 OB-Re Jak-STAT Pathway of Leptin Receptor Signal Transduction Ob-Ra Ob-Rb Jak2 Y Y Y Jak2 Y Y Y Leptin P Jak2 P Y Y P Y Jak2 P Y YP Y P P P SHP-2 P STAT3 P Jak2 P Y Y P Y Moves to Nucleus Jak2 YP YP Y P Hypothalamic signaling pathways regulating energy homeostasis Severe postnatal obesity of a child with leptin mutation Age (years) One example of human leptin mutation Leptin treatment of a girl with leptin deficiency SUMMARY • Most tissues are endocrine glands and have the capacity to secrete molecules that act on other tissues • All hormones act by interaction with their receptors • The action of most hormones are regulated by a negative feedback mechanism
