Slide 1Growth is key to survivalGH secreted from the anterior pituitaryGrowth hormone signalingGH works with IGF1IGF1 signalingThere are SIX IGF binding proteinsThe activities of GH and IGF1 are very hard to separateGH/IGF1 in skeletal muscle & other tissuesAdipose tissue: GH dominatesLiver is the major target of GHIGF1: paracrine & endocrine effectsIGF1: Bone growthGrowth hormone regulationTemporal controlSlide 16Hypothalamic control of GH releaseMany factors influence GH levelsThe other face of anabolism?GH/IGF1 + insulin balance stores & developmentGH/IGF1 + insulin balance stores & developmentWhy is GH considered counter regulatory to insulin?Normal variation in adult heightGrowth syndromesGenetic short stature syndromesTreatment of short stature with GHHormonesReview questionsNotesNotes (cont.)PGY452/552: Endocrine physiology9. Growth hormone & IGF1: the other face of anabolismA. Growth hormone & IGF1 work togetherB. Metabolic effectsC. ControlD. Integration with anabolismE. Growth syndromesGrowth is key to survivalLarge?Small?2 hormonesGrowth hormone Insulin-like growth factor 1Major Functions Protein anabolism  Lipid & glucose catabolism DNA/RNA synthesis MitogenesisLinear growth bone growth2GH secreted from the anterior pituitaryGH = somatotrophin190 amino acid peptide Secreted bySomatotrophs in anterior pituitary Most abundant cell typeExtensive hypothalamic controlReceptors most abundant in liverAlso muscle > adipose > kidney & heartWide-spread3HypothalamusHypothalamusGrowth hormone signalingGrowth hormone BP55 kDa soluble fragment of its receptor30-40% boundt½ ≈ 20 min Long for a peptide4GHGHGHJAKJAKGHPol IIPPPPPPPPSTATPPPP± ± JAK2/STAT3Most effects transcriptionalGH5GH works with IGF1IGF=insulin-like growth factor AKA somatomedin 68 amino acid peptideIGF1 actually causes growthMade in most tissues → paracrine or autocrine Liver: circulating IGF1 → endocrineIGF1 receptors widespreadIGF1 signaling6TKITKTKTKIGF1IGF1IGF1Similar hormones = similar receptorsAffinitiesIGF1R: IGF1 100x > insulinIR: insulin 100x > IGF1Signaling the sameBiochemically interchangeablePhysiologically distinct●Affinities●Concentrations●Localization of hormoneLocalization of signaling componentsIGF1 receptorIGF1 receptorInsulin receptorInsulin receptorThere are SIX IGF binding proteinsVery high affinity for IGF > than IGF1RIGF independent activitiesSome have many other interactionsIGFBP receptorIGF1 binding protein binding protein Prevents IGF diffusionParacrine activitiesReleased by specific proteases71122IGF1IGF1TKTKIGF1IGF1BPBPt1/2 = 12 hrt1/2 = 100 min t1/2 = 10 minparacrineendocrineIGF1The activities of GH and IGF1 are very hard to separateIGF1 expressed in all tissuesGHR and IGF1R expressed in all tissuesThe most important function of GH is IGF1 expression8GH/IGF1 in skeletal muscle & other tissues9JAKJAKGHPol IIGHIGF1TK TKPPPPPPPPPPPPSTATPPPPPPPPIGF1Pol IIGH/IGF1 transcriptional programGH/IGF1 transcriptional program44Glucose uptake(muscle)Glucose uptake(muscle)Amino AcidsProteinsProteins Protein anabolism Protein anabolismDNA/RNA synthesisMitogenesisDNA/RNA synthesisMitogenesisAAAAAAAAAAAA Tissue mass Tissue massAdipose tissue: GH dominates10JAKJAKGHPol IIPPPPPPPPSTATPPPP± ± GH1.  Glucose anabolism1.  Glucose anabolism11442.  TAG catabolism to fuel anabolism2.  TAG catabolism to fuel anabolism222a2a2b2bHSL Adipose mass Adipose massPKAPKAcAMPcAMPcAMPcAMPNEFANEFATAGTAGACβγαsHcAMP GLUT4 GLUT4 Hormone-sensitive lipase Hormone-sensitive lipaseAdenylyl cyclaseAdenylyl cyclaseLiver is the major target of GH11JAKJAKGHGHPPPPPPPPPol IISTATGHPyruvate2Glucose catabolismGlucose catabolismGHParacrine IGF1Paracrine IGF1IGF1BPBPIGF1IGF1TK TKPPPPIGF1PPPol IIITKTKIPPPPPol IIPPIGF1InsulinCirculating (endocrine) IGF1requires insulinCirculating (endocrine) IGF1requires insulin•GH: IGF1 transcription•IGF1+Insulin: circulating IGF1 binding protein•GH: IGF1 transcription•IGF1+Insulin: circulating IGF1 binding proteinIGF112IGF1: paracrine & endocrine effectsBone[or other tissue]Bone[or other tissue]Liver circulating IGF1oGH feedbackoOther (?)Liver circulating IGF1oGH feedbackoOther (?)Paracrine or autocrine effects cause growthParacrine or autocrine effects cause growthGHGHIGF1IGF1: Bone growthIGF1: secreted from & stimulates dividing chondrocytes in the epiphyseal plateIGF1: secreted from & stimulates dividing chondrocytes in the epiphyseal plateEpiphysisDiaphysisBone growthDividing chondrocytesEpiphyseal plateEpiphyseal plate closed by estrogen →bone growth stopsEpiphyseal plate closed by estrogen →bone growth stops13The difference is two amino acids in the IGF1 receptorThe difference is two amino acids in the IGF1 receptorGrowth hormone regulationGrowth hormone regulationMany levels of regulation•HPA•Lifetime•OtherMany levels of regulation•HPA•Lifetime•Other14Temporal controlCircadian Night w/ sleep!DevelopmentalAverage [GH] reflected in [IGF1] [IGF1/GH] levels Peak about age 12Peak of growth rateFor GH:  pulse rate @ peak IGF1 levels15GH (mg/liter)NightHypothalamusGrowth hormone releasing hormone (GHRH)●43 amino acid peptide●Coupled to GαsSomatostatin (GHIH)●14 amino acid peptide●28 amino acid form made in liver●Coupled to Gαi AntagonisticExtensive feedbackExact loops unclearNote ultrashort16GHRHGHIHGHIGF1??GHRH most important → severing infundibulum  GH secretion GHRH most important → severing infundibulum  GH secretion Hypothalamic control leads to complex feed back loops for GH expressionHypothalamic control of GH release17Control of both transcription & release allows both short (pulses) & long-term regulationControl of both transcription & release allows both short (pulses) & long-term regulationGHGHNote the opposing actions of Gαs and GαiNote the opposing actions of Gαs and GαiCa2+Ca2+βγαsGHRHGHIHACPKAPKAATPαi βγPKAiPKAicAMPcAMPcAMPPKAiPKAicAMPcAMPPPGHIH has more influence on pulses than synthesisGHIH has more influence on pulses than synthesisPol IIPPSleepSleepMany factors influence GH levels18GHRHGHIHMost work through regulation of GHIH or GHRH or bothMost work through regulation of GHIH or GHRH or