PGY452 552 Endocrine physiology 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 regulated by insulin Long term TAGs in adipose tissue regulated by caloric input vs output Current view Insulin other hormones reflect long term status of energy stores Adipose stores 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 Caloric intake is constant Abundance is the rule Humans are 250 000 years old Very recent situation Caloric intake inconsistent Famine common Unpredictable energy demands Development Reproduction Environment Survival depended on balancing caloric intake with long term energy demands despite long term unknowns 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 Adipokines Communicate regulate status of energy stores Adipose GI Pancreas 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 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 Monocyte Chemo attractant Protein 1 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 This does not produce is mouse continuously added Important in humans Mutations induce obesity Receptor mutations induce obesity ob ob mice can be treated with leptin leptin ob ob phenotype 6 Leptin communicates status of energy stores to the hypothalamus adipocyte hypertrophy proliferation Stores Leptin Energy Intake Leptin Permissive for use of adipocyte energy stores 7 Leptin signals by a tyrosine kinase STAT3 binds to the receptor associated receptor phosphorylated phosphorylated dimerizes Leptin binding autophosphorylation of JAK2 TK receptor L L JAK Just another kinase STAT Signal transducers activators of transcription P P 4 JAKs 7 STATs GASE g activated site element P JAK P P P JAK JAK P P P ST AT P JAK P Pol II Activated STAT GASE 8 Why the hypothalamus Tied to hunger centers Sensory input Higher order functions Planning Anticipation Other hormones Ghrelin Insulin Many others Leptin 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 Ghrelin stimulates intake through hypothalamus dorsalvagal complex Everything else inhibits CCK Ghrelin GLP1 Insulin PP Amylin PYY oxyntomodulin Stretch Leptin Insulin GLP1 Satiety peptide hormones Stretch Considerable amount is known about neurobiology 11 Common endocrine target 2 hypothalamic pathways Anorexigenic or satiety center POMC neurons Energy Intake Hunger Allows use of adipose TAG stores Energy out Anorexigenic Satiety intake Maintain consume stores Orexigenic Feeding intake Protect expand stores Orexigenic or feeding center Default pathway AgRP NPY neurons Energy intake Hunger Conserves fat stores Stimulates adipocyte development proliferation Energy out POMC neurons AgRP NPY neurons 12 Many levels of control AgRP key to making orexigenic the default pathway Anorexigenic Satiety intake Orexigenic Feeding intake Maintain consume stores aMSH Protect expand stores NPY AgRP Reproductive drive Pleasure reward system Stress Glucose other nutrients POMC neurons Glucose other nutrients DVC AgRP NPY neurons Satiety peptides Leptin Insulin GLP1 Ghrelin 13 Anorexigenic Pathway well fed Anorexigenic Energy intake Energy stores Pleasure reward system Orexigenic aMSH Large stores secrete lots of leptin High food intake POMC AgRP NPY Ghrelin Leptin GLP1 Satiety peptides Leptin insulin others Insulin insulin GLP1 satiety peptides Ghrelin Satisfaction AgRP POMC Satiety maintenance of stores 14 Orexegenic pathway poorly fed Low stores leptin Low intake insulin SPs Ghrelin desire to eat AgRP POMC Hunger Stores adipocyte proliferation Pleasure reward system Anorexigenic Orexigenic Energy intake Energy stores AgRP NPY POMC AgRP NPY Ghrelin Leptin Insulin GLP1 Satiety peptides 15 Hormones Hormone Source Type t min Rcpt Stimulus Inhibition Major Effects Leptin Adipose Glycoprotein 90 TKA adipose mass glucose GLP1 GIP adipose mass hypothal satiety centers hypothal hunger centers ANABOLISM Liver Glucokinase Muscle Adipose GLUT4 Insulin Pancreatic cells Peptide 5 RTK Ghrelin Stomach Peptide 20 G q unclear N A hypothal hunger centers GLP 1 GI Peptide 2 G S oral glucose N A insulin glucose TKA is tyrosine kinase associated There is a lot of stuff in here that it would be 16 Review questions 1 How has our current view of the regulation of adipose energy stores evolved from previous ideas 2 What evidence suggests leptin is important in humans 3 How do leptin levels vary with the state of adipose energy stores 4 What are the main hormones of the energy intake system and what is their influence on the POMC and AgRP pathways 5 How do the neurotransmitters melanocyte stimulating hormone MSH and Agoutirelated peptide AgRP regulated the activity of the anorexigenic and orexigenic centers 17 NOTES There is a big caveat to this topic This is the 10th year I ve taught this topic and things have changed considerably Our understanding of this system may continue to evolve There are many unknowns or more precisely poorly understood o Leptin receptors are present in many tissues other roles Immune Reproductive Glycemic control o o o o Slide 5 listed 22 adipokines other than leptin They all have a role in mice and they all exist in humans but what are they doing if anything With the exception of a handful of mutant genes in humans almost all these studies were done in mice is this data relevant