Slide 1Brave new world of endocrinologyLong-term regulation is (was) necessaryEnergy signals come from energy storesThere are many adipokinesLeptin is the key adipokineLeptin communicates status of energy stores to the hypothalamusLeptin signals by a tyrosine kinase associated receptorWhy the hypothalamus?Ghrelin stimulates appetiteEnergy intake control systemCommon endocrine target: 2 hypothalamic pathwaysMany levels of controlAnorexigenic Pathway: well fedOrexegenic pathway: poorly fedHormonesReview questionsNOTESNotes (cont.)Notes (cont.)PGY452/552: Endocrine physiology7. Regulation of long-term energy storesA. The issue of balanceB. Leptin regulates adipose homeostasisC. Other players1) Insulin2) GhrelinD. Hypothalamic integrationBrave 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 key2Long-term regulation is (was) necessaryModern humans (in the developed world) Food ●Caloric intake is constant●Abundance is the ruleVery recent situationHumans are 250,000 years oldCaloric intake inconsistentFamine commonUnpredictable energy demandsDevelopmentReproductionEnvironment3Survival depended on balancing caloric intake with long term energy demands despite long term unknownsSurvival depended on balancing caloric intake with long term energy demands despite long term unknownsGIGIEnergy 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AdipokinesCommunicate & regulate status of energy stores4HypothalamusHypothalamusAdiposeAdiposePancreasPancreasThere are many adipokines5LeptinLeptinVisfatinRetinol binding protein 4ResistinPalmitoleateChemerinMonocyte Chemo-attractant Protein 1ApelinOmentinAll peptides (almost)Partial listUndetermined function in humansExcept LEPTINAll peptides (almost)Partial listUndetermined function in humansExcept LEPTINAdiponectinDesnutrinAutoxinTNFα Interleukin-6APR-GFHepatic GFVEGFVaspinPLUSAngiotensinogenSerum amyloid ATumor necrosis factor αPlasminogen activator inhibitor 1Zinc α2 glycoproteinLeptin 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 leptinThis mouse does not produce leptin (ob/ob phenotype)6Leptin communicates status of energy stores to the hypothalamus Leptin Leptin Leptin Leptin Energy Intake Energy IntakeStores7 adipocyte hypertrophy & proliferationPermissive for use of adipocyte energy storesPermissive for use of adipocyte energy storesLeptin signals by a tyrosine kinase associated receptor JAK: Just another kinaseSTAT: Signal transducers & activators of transcription4 JAKs & 7 STATsGASE: g-activated site element8GASELeptin binding → autophosphorylation of JAK2 TK → receptorLeptin binding → autophosphorylation of JAK2 TK → receptorSTAT3 binds to the receptor → phosphorylated → dimerizesSTAT3 binds to the receptor → phosphorylated → dimerizesJAKJAKLActivated STATActivated STATPPPPPPPPPPJAKJAKLPPPPSTATPPPPPol IIPPPPWhy the hypothalamus?Tied to hunger centersSensory inputHigher order functions●Planning●AnticipationOther hormonesGhrelinInsulinMany othersComplex input9LeptinLeptinGhrelin stimulates appetite28 amino acid peptideReceptor: Gαq coupled → Ca2+ release & PKC activationSecreted from the fundus of the stomach In response to parasympathetic signalsMechanism of release not knownStimulates appetite10FundusDuodenumEsophagusβγαqPKCCa2+Energy intake control systemGhrelin stimulates intake through hypothalamus & dorsal-vagal complexEverything else inhibitsLeptinInsulinGLP1Satiety peptide hormonesStretchConsiderable amount is known about neurobiology11Dorsal-vagal complexDorsal-vagal complexPYYoxyntomodulinPYYoxyntomodulinPPAmylinPPAmylinLeptinLeptinInsulinInsulinHypothalamusHypothalamusGLP1GLP1CCKCCKGhrelinGhrelinStretchStretchCommon endocrine target: 2 hypothalamic pathwaysAnorexigenic or satiety center: POMC neurons Energy Intake● Hunger●Allows use of adipose TAG stores● Energy outOrexigenic or feeding centerDefault pathwayAgRP/NPY neurons Energy intake● Hunger●Conserves fat stores●Stimulates adipocyte development & proliferation● Energy out12AgRP/NPYneuronsPOMC neuronsOrexigenicFeeding:intake(Protect/expand stores)AnorexigenicSatiety: intake(Maintain/consume stores)Many levels of control13AgRP/NPYneuronsPOMC neuronsOrexigenicFeeding:intake(Protect/expand stores)AnorexigenicSatiety: intake(Maintain/consume stores)aMSHaMSHAgRPAgRPNPYNPYInsulinInsulinGhrelinGhrelinLeptinLeptinGLP1GLP1Reproductive driveReproductive driveSatiety peptidesSatiety peptides Glucose & other nutrients Glucose & other nutrientsDVCPleasure/reward systemPleasure/reward systemStressStress Glucose & other nutrients Glucose & other nutrientsAgRP key to making orexigenic the default pathwayAgRP key to making orexigenic the default pathwayAnorexigenic Pathway: well fedLarge stores secrete lots of leptinHigh food intakeinsulinGLP1 & satiety peptidesGhrelinSatisfactionLeptin & insulin (& others) AgRP POMCSatiety & maintenance of stores14AgRP/NPYAgRP/NPYPOMCPOMCAnorexigenic Energy intake Energy storesAnorexigenic Energy intake Energy storesSatiety peptidesSatiety peptidesLeptinLeptinGLP1GLP1InsulinInsulinaMSHaMSHGhrelinGhrelinPleasure/ reward systemPleasure/ reward systemOrexigenicOrexigenicOrexegenic pathway: poorly fedLow stores → leptinLow intake → insulin & SPsGhrelin & desire to eat AgRP→ POMC Hunger  Stores adipocyte