PGY452 552 Endocrine physiology 9 A B C D E Growth hormone IGF1 the other face of anabolism Growth hormone IGF1 work together Metabolic effects Control Integration with anabolism Growth syndromes Growth is key to survival Large Small 2 hormones Major Functions Growth hormone Insulin like growth factor 1 Protein anabolism Lipid glucose catabolism DNA RNA synthesis Mitogenesis Linear growth bone growth 2 GH secreted from the anterior pituitary Hypothalamus 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 spread 3 GH GH Most effects transcriptional P JAK P JAK P P STAT GH Growth hormone signaling GH JAK2 STAT3 Growth hormone BP P Pol II 55 kDa soluble fragment of its receptor 30 40 bound t 20 min Long for a peptide 4 P GH works with IGF1 IGF insulin like growth factor IGF1 actually causes growth AKA somatomedin 68 amino acid peptide Made in most tissues paracrine or autocrine Liver circulating IGF1 endocrine IGF1 receptors widespread 5 Similar hormones similar receptors Affinities IGF1R IGF1 100x insulin IR insulin 100x IGF1 Signaling the same Biochemically interchangeable Physiologically distinct I IGF1 IGF1 IGF1 signaling IGF1 TK TK IGF1 receptor TK TK Insulin receptor Affinities Concentrations Localization of hormone Localization of signaling components 6 There are SIX IGF binding proteins IGF1 binding protein binding protein Some have many other interactions IGFBP receptor Prevents IGF diffusion Paracrine activities Released by specific proteases t1 2 10 min IGF1 IGF1 IGF1 t1 2 100 min IGF1 IGF1 Very high affinity for IGF than IGF1R IGF independent activities BPBP paracrine endocrine 1 TK TK t1 2 12 hr 2 7 IGF1 expressed in all tissues GHR and IGF1R expressed in all tissues The most important function of GH is IGF1 expression The activities of GH and IGF1 are very hard to separate 8 GH IGF1 in skeletal muscle other tissues IGF1 GH P JAK P Glucose uptake muscle 4 P TK TK P JAK P Amino Acids Protein anabolism DNA RNA synthesis Mitogenesis AAAAAAAAAAAA P STAT 4 P IGF1 P Pol II P Pol II GH IGF1 transcriptional program Tissue mass Proteins 9 P Adipose tissue GH dominates 1 Glucose 1 anabolism GH H 4 GLUT4 P JAK JAK P Adenylyl cyclase 2 TAG catabolism 2 to fuel anabolism 2a s AC P cAMP P ST AT 4 NEFA PKA cAMP cAMP HSL cAMP cAMP Adipose mass P 2b Pol II TA G Hormonesensitive lipase 10 P Liver is the major target of GH 2 P JAK P JAK P P TK TK P P TK P TK P IGF1 Insulin Pol II P Pol II IGF1 GH GH IGF1 transcription IGF1 Insulin circulating IGF1 binding protein GH Pyruvate IGF1 BPBP STAT Glucose Glucose catabolism catabolism IGF1 GH Paracrine IGF1 II IGF1 Circulating endocrine IGF1 requires insulin P Pol II 11 IGF1 paracrine endocrine effects Paracrine or autocrine effects cause growth IGF1 Bone or other tissue GH GH Liver circulating IGF1 o GH feedback o Other 12 IGF1 Bone growth IGF1 secreted from stimulates dividing chondrocytes in the epiphyseal plate Bone growth Dividing chondrocytes Epiphysis The difference is two amino acids in the IGF1 receptor Epiphyseal plate Diaphysis Epiphyseal plate closed by estrogen bone growth stops 13 Growth hormone regulation Many levels of regulation HPA Lifetime Other 14 Temporal 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 levels Night GH mg liter 15 Hypothalamic control leads to complex feed back loops for GH expression Hypothalamus Growth hormone releasing hormone GHRH 43 amino acid peptide Coupled to G s Somatostatin GHIH 14 amino acid peptide 28 amino acid form made in liver Coupled to G i Antagonistic Extensive feedback Exact loops unclear Note ultrashort GHRH GHIH IGF1 GH GHRH most important severing infundibulum GH secretion 16 Hypothalamic control of GH release GHRH Ca2 GHI H s AC cAMP i P ATP Ca2 cAMP cAMP cAMP cAMP GH PKAii PKA PKAii Note the opposing actions of G s and G i GHIH has more influence on pulses than synthesis P Pol II GH Control of both transcription release allows both short pulses long term regulation 17 Many factors influence GH levels Most work through regulation of GHIH or GHRH or both Energy stores leptin GH NEFAs GH Circadian GHIH GHRH Fasting Starvation Short term stress Exercise Glucose AMINO ACIDS Long term stress Cortisol GH Sleep Sex steroids Thyroid hormone Ghrelin 18 The other face of anabolism GH IGF1 have a complex relationship with insulin Insulin GH IGF1 act at different points to increase protein synthesis Opposing effects on GLUT4 Liver IGF1 production is very low in the absence of insulin Circulating IGF binding protein GH due to loss of IGF1 feedback Amino Acids GH I I GH Proteins 19 GH IGF1 insulin balance stores development Starvation Low quality Abundance Amino acids Glucose Fats GH Insulin IGF1 Protein anabolism Mobilize energy for growth Amino acids Amino acids Glucose Fats Glucose Fats Insulin GH IGF1 Glucose uptake Mobilize energy for storage Insulin GH IGF1 Protect protein muscle Consume fat for survival 20 GH IGF1 insulin balance stores development In times of high nutritional value food abundance o Protein consumption results in high amino acids stimulating GF IGF1 synthesis o CHO fat consumption stimulates insulin IGF binding protein IGFBP synthesis o If other factors are favorable Ghrelin encouraging more consumption leptin signaling that stores are sufficient these conditions favor mobilization of energy for growth When only poor quality food is available low protein o CHOs favor GH inhibition and there is no protein signal Therefore IGF production is reduced o Insulin is favored by the CHOs IGFBP synthesis doesn t matter in the absence of IGF o GLUT4 induction favors energy storage When little food is available o Neither GH nor insulin synthesis is favored o If this becomes starvation protein catabolism is favored amino acids in the blood Plus there are likely other factors secreted perhaps an adipokine so that GH synthesis is induced o However IGF synthesis stays low because of lack of IGFBP o This allows GH to slow the catabolism in an attempt to preserve enough muscle to survive 21 Why is GH considered counter regulatory to insulin Growth hormone Glucose catabolism GLUT4 transcription Liver gluconeogenesis Adipose lipid catabolism Insulin Glucose anabolism Adenylyl cyclase transcription Hormone sensitive lipase