PGY452 552 Human Physiology Endocrinology 7 Regulation of Longterm Energy Stores A The issue of balance B Leptin regulates adipose homeostasis C Other players 1 Insulin 2 Ghrelin D Hypothalamic integration Brave new world of endocrinology Traditional view of energy homeostasis Short term Carbohydrates as liver glycogen Long term TAGs in adipose tissue lipid droplets Insulin glucagon regulate CHO stores Adipose stores regulated by caloric input vs output Current view Insulin Glucagon other hormones reflect long term status of energy stores Carbohydrates have wider influence Adipose stores Homeostatic Regulating through interactions with CNS Hormones from adipose GI pancreas likely other tissues Insulin is key 2 Long term regulation is was necessary Modern humans in the developed world Food Very recent situation Humans are 250 000 years old Caloric intake is constant Abundance is the rule Caloric intake inconsistent Famine common Survival depended on balancing caloric intake with long term energy demands despite long term unknowns Unpredictable energy demands Development Reproduction Environment 3 Energy signals come from energy stores Adipose tissue is the main site of stored energy Amount varies widely 35 genetics Almost unlimited storage capacity Energy stored proportional to size Essential Adipose an is an endocrine tissue Adipose hormones Hypothalamus Adipose GI Pancreas Adipokines Communicate status of energy stores 4 There are many adipokines PLUS Interleukin 6 Desnutrin Resistin Palmitoleate Autoxin Vaspin Adiponectin Leptin Visfatin TNF Retinol binding protein 4 APR GF Chemerin Omentin VEGF Apelin Hepatic GF Monocyte Chemo attractant Protein 1 Angiotensinogen Serum amyloid A Tumor necrosis factor Plasminogen activator inhibitor 1 Zinc 2 glycoprotein All peptides almost Partial list Undetermined function in humans Except LEPTIN 5 Leptin is the key adipokine Discovered in mutant mice by Jeffrey Freedman in 1994 165 amino acid peptide Leptin with adipose mass In the absence of leptin adipose tissue is continuously added Important in humans Mutations induce obesity Receptor mutations induce obesity ob ob mice can be treated with leptin 6 Leptin communicates status of energy stores to the hypothalamus Stores Leptin Leptin Energy Intake Energy Intake 7 Leptin signaling by tyrosine kinase associated receptor STAT binds to the receptor phosphorylated dimerizes Leptin binding autophosphorylation of JAK receptor L L P JAK P P P JAK P ST AT P JAK P P Pol II P Activated STAT GASE JAK P P JAK Just another kinase STAT Signal transducers activators of transcription GASE g activated site element 8 Why the hypothalamus Tied to hunger centers Sensory input Higher order functions Leptin Other hormones Planning Anticipation Ghrelin Insulin Perhaps many others Complex input 9 Ghrelin stimulates appetite 28 amino acid peptide Receptor G q coupled Ca2 release PKC activation Secreted from the fundus of the stomach In response to parasympathetic signals Mechanism of release not known Stimulates appetite Ca q 2 Esophagus Duodenum PKC Fundus 10 Energy intake control system Hypothalamus Dorsal vagal complex Leptin CCK Ghrelin GLP1 Insulin PP Amylin PYY oxyntomodulin Communicates status of energy stores intake to CNS Ghrelin stimulates intake Everything else inhibits Peptides in gray are satiety factors Considerable amount is known about neurobiology 11 2 hypothalamic pathways Intake hunger Intake satiety Ghrelin AgRP NPY hunger satiety neurotransmitter release from POMC CART neurons Pleasure reward system Energy intake hunger Energy intake satiety aMSH POMC Pleasure reward intake CART Leptin Insulin other peptides neurons NPY AgRP release Leptin insulin melanocyte stimulating Leptin hormone Insulin MSH energy intake AgRP NPY NPY AgRP neurons GLP1 Satiety peptides Ghrelin 12 Satiety Pathway Satiety Energy intake Energy stores POMC CART NPY AgRP Leptin Insulin GLP1 Satiety peptides Large stores secrete lots of leptin High food intake results in lots of satiety peptides insulin Leptin insulin NPY AgRP POMC CART Satiety maintenance of stores 13 Hunger Pathway Low stores leptin Low intake insulin SPs Ghrelin desire to eat AgRP POMC CART Hunger Stores adipocyte proliferation Feedback to anticipatory signals Satiety pleasure reward POMC CART Hunger Energy intake Energy stores NPY AgRP Ghrelin 14 Many unknowns A coherent view of adipose homeostasis Leptin receptors present in many tissues other roles Immune Reproductive Glycemic control Roles of all those adipokines How CNS feedback to adipose works Many genetic alleles of unknown function Unknown Unknowns 15 Summary Long term regulation of energy stores The Hormones Hormone Source Leptin Adipose Insulin N A not applicable Type t Glyco 90 protein Rcpt Stimulus Inhibition Major Effects hypothal satiety centers hypothal hunger centers ANABOLISM Liver Glucokinase Muscle Adipose GLUT4 Other JAK adipose mass N A Pancreatic Peptide 5 cells TK glucose GLP1 GIP glucose Ghrelin Stomach Peptide 20 G q unclear N A hypothal hunger centers GH GLP 1 GI Peptide 2 G S oral glucose N A insulin hypothal hunger centers N A hypothal hunger centers Don t worry about the name of all those neuropeptides 16 Review questions 1 2 3 4 How is the current view of adipose energy stores different from the previous view What evidence suggests leptin is important in humans How do leptin levels vary with the state of adipose energy stores What are the main hormones of the energy intake system and what is their influence on the POMC CART satiety and NPY AgRP hunger pathways 17 Slide 4 Adipokine a hormone secreted from the adipose tissue Slide 5 The only adipokine you need to know is leptin Slide 8 You don t know to know the full names of JAK STAT GASE Slide 11 You re not responsible for the satiety peptides in gray They are peptide YY and oxyntomodulin from intestinal L cells cholecystokinin CKK from I cells pancreatic peptide PP and amylin from the pancreas Satiety is a feeling of fullness or sufficiency Slide 12 Don t worry about the names of the neurotransmitters It is sufficient to know that there are two pathways and the influence that Ghrelin Leptin and Insulin have on those pathways FYI MSH a melanocyte stimulating hormone POMC Pro opiomelanocortin CART Cocaine and amphetamine stimulated transcript peptide NPY Neuropeptide Y AgRP Agoutirelated peptide Slide 15 There s nothing to test you on here I just presented it to let you know the state of what I consider a very important area As