Endocrine Function 2: Control of Metabolism (Growth and Thyroid) PDF
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Fernando Gomez-Pinilla, PhD
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Summary
This document covers endocrine function 2, focusing on the control of metabolism, specifically growth and thyroid regulation. It details the hypothalamus-pituitary axis, growth regulation, and somatotropic axis hormones. The document also explores GH regulation, IGF-1, and potential disruptions in the somatotropic axis.
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Endocrine func,on 2: control of metabolism (growth and thyroid) Neural Control of Physiological Systems (C144/244) November 9, 2022 Fernando Gomez-Pinilla, PhD 1 Hypothalamus-pituitary axis regulates crucial survival functions – Growth –...
Endocrine func,on 2: control of metabolism (growth and thyroid) Neural Control of Physiological Systems (C144/244) November 9, 2022 Fernando Gomez-Pinilla, PhD 1 Hypothalamus-pituitary axis regulates crucial survival functions – Growth – Metabolism – Stress – Reproduc,on – Circadian rhythms general body homeostasis 2 Growth Regula,on: Somatotropic Axis 14 Growth Regula,on: Somatotropic Axis 15 Somatotropic axis controls growth and development • Neonatal and postnatal growth (pubertal) – S,mulated growth is sexually dymorphic • Growth hormone (GH) stimulates cri,cal functions related to metabolic homeostasis: • protein synthesis, lipolysis, carbohydrate metabolism, glucose uptake and u,liza,on; • growth of organs: heart, kidney, skeletal growth and matura,on, • immune func,on and hormones. 18 The somatotropic axis hormones • Hypothalamus (arcuate nucleus): Growth hormone releasing hormone (GHRH) • Hypoth- GH inhibi,ng hormone • (somatosta,n) • Pituitary: GH or somatotropin • Liver: Insulin-‐like growth factor 1 (IGF-‐1) • GH and IGF-‐1 have somatotropic ac,ons on target ,ssues undergoing growth, regenera,on, or metabolism such as bone and muscle 16 GH has (-‐) feedback on GHRH secre,on and (+) ac,on on somatosta,n Somatosta,n is downregulated in the absence of GH feedback 17 GHRH neurons • GHRH neurons are in arcuate nucleus and send axons to other hypoth nuclei besides ME, i.e., regulates feeding – Receive inputs from other brain regions • Somatosta,n neurons are disperse throughout CNS, but those regula,ng GH release are in the ant hypoth. • Somatosta,n neurons are affected by metabolic ac,ve substances ((+) aa, (-‐) FA and glucose) 21 GHRH receptor interac,on • GHRH comes from a precursor protein, preproGHRH • GHRH receptor is a G-‐protein that ac,vates cAMP, synthesis and release of GH from pituitary. • There are 5 somatosta,n receptors, involving an inhibitory G protein causing hyperpolariza,on 20 GH regula,on • • • Regula,on of GH also involves neurotransmiMers: dopamine, vasoac,ve intes,nal pep,de, TRH, galanin, NPY, interleukins Hormonal regula,on of GH: thyroid, glucocor,coids, sex steroids, metabolic fuels. Half of GH in circula,on is bound to GH-‐binding protein-‐-‐addi,onal regula,on 22 GH has pulsa,le and daily (nocturnal during sleep) pattern release: • Pulse frequency of GHRH is every 1-‐3 h • GH released in connection with sleep in humans suggesting that • sleep is a restorative process 19 IGF-‐1 • IGF-1 is synthesized in liver and exerts a (-‐) feedback on GHRH suppresing its release and GH • IGF-1 is also produced in brain acting as a growth factor • IGF-1 can also s,mulates somatosta,n release • It binds several IGF binding proteins (IGFBP) – free IGF-‐1 has more biological ac,vity 23 Disrup,ons of the somatotropic axis • muta,ons in the IGF-‐1 or GH systems during development: dwarfism • GH oversecre,on during development: giantism • GH oversecretion during adulthood results in acromegaly (,ssue from jaws, nose, orbital ridges, fingers, elbows, knees most sensi,ve) 24 acromegaly dwarfism giantism 25 Implica,ons for mind-‐body interac,on The capacity of the brain to regulate hormones that influence the body The capacity of body hormones to influence the brain 26 The brain-‐pituitary-‐thyroid axis • Controls metabolic ac,vity and calorigenic processes in target cells – Oxygen consump,on, basal metabolic rate, body weight, ATP produc,on in mitochondria, protein synthesis • Important role during development – Deficiency impairs nervous system, growth and bone development 6 • Thyrotropin releasing hormone (TRH) in the PVN • Thyrotropes (contain TRH receptor) make up 10% of cells in anterior pituitary • Release thyroid s,mula,ng hormone (TSH) 7 Triiodothyronine (T3) binds to TRs & mediates neg feedback Deiodinase I & II (I: peripheral ,ssue, pituitary; II: brain, pituitary, brown adipose ,ssue) Thyroxoine (T4) mostly converted to T3, also mediates neg feedback < 1% of T3 and T4 in circula,on not bound to globulin (free) 8 Hypothalamus PVN Parvocellular part Thyrotropin Releasing Hormone Suprachiasmatic N. circadian rhythms Nocturnal TSH surge External layer of median eminence Adenohypothesis Thyrotropes Thyroid Stimulating Hormone Triiodothyronine (T3) Thyroxine (T4) Thyroid Gland 9 TSH receptor 11 Thyroid hormone receptors (TR) • Nuclear hormone superfamily – Form heterodimers that bind to DNA and regulate transcrip,on • Receptors throughout the brain, peripheral and autonomic NS, pituitary gland, bone, muscle, liver, heart, tes,s, lung, placenta… • Several splice variants (α1, α2, β1, β2) 12 Thyroid Disorders • Hypothyroidism: sleep apnea, hypothermia, hypoven,la,on, depression, peripheral neuropathy, cerebellar ataxia, coma, myxedemia, high ch olesterol • Hyperthyroidism: tremor, insomnia, seizures, cogni,ve and psychiatric impairments, manic-‐depressive symptoms, chorea, coma, low exercise tolerance • Cre,nism, deficiency during fetal or early development: deficits in neurological, mental, and physical development • Goitre, major cause is iodine deficiency • Hashimoto’s thyroidi,s – autoimmune disease in which thryroid gland gets destroyed resul,ng in hypothyroidism • Graves Disease.-‐ autoan,bodies that s,mulates TSH receptors resul,ng in hyperthyrodism 13
