Hormones & Metabolism YR1 Lecture PDF

Hormones & Metabolism Associate Professor David A Mahns Associate Dean, Research School of Medicine Western Sydney University [email protected] Objectives: - To provide an overview - Insulin and Glucagon - Cortisol - Thyroid Hormones - Adrenaline - To move from Simple feed-back loop → Lay...

Hormones & Metabolism Associate Professor David A Mahns Associate Dean, Research School of Medicine Western Sydney University [email protected] Objectives: - To provide an overview - Insulin and Glucagon - Cortisol - Thyroid Hormones - Adrenaline - To move from Simple feed-back loop → Layered / Integrated systems - To Illustrate how these systems can redistribute different energy sources (glucose, amino acids, lipids) and energy usage. Two broad systems exist to communicate and coordinate body functions 1. Neural system: this is a system of neve fibres, tracts and interconnected networks that process information and account for rapid - short term reactions to the world. 2. Endocrine system: this system integrates organ function by releasing Hormones into the circulation. Review –earlier lecture ‘Communication systems’ Endocrine system: Hormones Peptides: Insulin, Glucagon, Angiotensin II. Steroids: gluco-corticoids (Cortisol) mineral-corticoids (aldosterone), Androgens (testosterone), progesterone, Estrogen. Amino Acid Hormones:Thyroxine (T4) Triiodothyronine (T3). Amines: Adrenaline, Noradrenaline. This lecture Endocrine On distant tissues -Transported in the Circulation Paracrine Adjacent / surrounding cells in same tissue Autocrine Same cell Auto feed back Hormones binds to specific receptors that have organ/tissue specific distributions leading to specific responses (specificity) in the target cell. Intracellular/ Nuclear receptors - Lipid soluble - a must (ie cross lipid bi-layer) Intra cellular / Nuclear receptors ➔ Slow onset / longer term changes (minutes - hours → hours –days) ➔ Changes in protein / gene expression Trans membrane receptors i) ligand-gated ion channel Ach → Na+ entry →Opening of ion channel →eg neuromusclular transmission ii) G-Protein coupled/ Second messenger Receptors iii) Catalytic receptors →Accumulation of cAMP → Phoshorylation / →Cascade of enzyme activation of enzymes activation →Amplification of Rapid onset / short term changes response second - minutes → minutes - hours Transmembrane /Extracellular receptors Most hormones bind to extracellular receptors according to the following steps: Recognition: Specific chemical / physical interactions (lock – key) Transduction: Extracellular binding leads to a conformational change that may i) directly activates an ion channel (ligand-gated ion channel, Na+ entry) ii) modulates inherent catalytic/enzymatic activity (Catalystic receptors) or iii) favours an interaction with membrane bound (G-Protein coupled receptors) or cytosolic enzymes (eg Protein Kinase A - PKA) All 3 actions may be trigged independently, or in parallel, and lead to the generation of second messengers. Response: represents the culmination of the response to the activation of receptor stimulation Termination: Effects must be reversible Simple Feed Back Loop (Insulin and Glucagon)  [Glucose] → βCell stimulation → Insulin Secretion →  Glucose uptake (muscle/liver) → ↓ [Glucose] Simple Feed Back Loop  [Glucose] → βCell stimulation → Insulin Secretion →  Glucose uptake (muscle) → ↓ [Glucose] Hierarchical Control Anterior Pituitary Hypothalamic Releasing (Inhibitory) Factor 0 Target Cell Hormone Released Target of Anterior Pituitary Hormone Somatotroph GH Multiple somatic tissues TRH Thyrotroph TSH Thyroid follicular cells, stimulated to make thyroid hormone CRH Corticotroph ACTH Fasciculata and reticularis cells of the adrenal cortex, to make corticosteroids GnRH Gonadotroph FSH Ovarian follicular cells, to make estrogens and progestins Sertoli cells, to initiate spermatogenesis GnRH Gonadotroph LH Ovarian follicular cells, to make estrogens and progestins Leydig cells, to make testosterone (inhibited by dopamine) Lactotroph PRL Mammary glands, initiates and maintains milk production GHRH (somatostatin) Posterior Pituitary Hormone Synthesized in Hypothalamus Hormone Released into Posterior Pituitary Target of Posterior Pituitary AVP AVP Collecting duct, to  water permeability Oxytocin Oxytocin Uterus and breast Hierarchical Central Control: Hypothalamic – Adrenal Axis Hypothalamus Pituitary Stalk Anterior Pituitary Small diameter nerves →Releasing factor → ‘portal’ circulation → Stimulate Troph cells → Release Hormones ACTH Posterior Pituitary or ‘neurohypophysis’ Large diameter nerves →Release Hormones Into Posterior Pituitary Vasopressin Oxytocin ACTH (pg/ml) Cortisol (mg/ml) Diurnal Rhythms Stress : Food deprivation Water deprivation & loss Physical Stress (exercise / trauma) Emotional Stress (Combat / exams / surgery) Biochemical Stress (diabetes / starvation) Cortisol – Origin Where: Specialised cells: - Adrenal Cortex Zona fasciculata Why these cells - enzymatic machinery to synthesise cortisol 20% de novo 80% LDL Cortisol –Synthesis Lipid Soluble diffuses across membrane Cytoplasmic Glucocorticoid receptors Translocate → nucleus Bind genes →  /↓expression Cortisol - mode of action - nuclear receptors CRH ACTH Adrenal Cortex → Cortisol → Cytoplasmic receptors → Translocate nucleus (eg Heat shock proteins) Circulation → Cytoplasm unbound Bind to 5’ genes →  /↓expression Glucocorticoids - Cortisol Anabolic effects Liver:  gluconeogenesis  enzyme synthesis Catabolic Effects Muscle Lymphoid Skin Adipose ↓ protein / nuclei acid synthesis  protein breakdown → AA ↓ Glucose uptake Cortisol - Regional Actions Liver –  Amino acids → Glucose (gluconeogenesis) Muscle –  breakdown of protein → amino acids Adipose tissue –  mobilisation of fatty acids Curiosity peripheral mobilisation → facial deposition→ Moon face. Immune suppression Anterior Pituitary Hypothalamic Releasing (Inhibitory) Factor 0 Target Cell Hormone Released Target of Anterior Pituitary Hormone Somatotroph GH Multiple somatic tissues TRH Thyrotroph TSH Thyroid follicular cells, stimulated to make thyroid hormone CRH Corticotroph ACTH Fasciculata and reticularis cells of the adrenal cortex, to make corticosteroids GnRH Gonadotroph FSH Ovarian follicular cells, to make estrogens and progestins Sertoli cells, to initiate spermatogenesis GnRH Gonadotroph LH Ovarian follicular cells, to make estrogens and progestins Leydig cells, to make testosterone (inhibited by dopamine) Lactotroph PRL Mammary glands, initiates and maintains milk production GHRH (somatostatin) Posterior Pituitary Hormone Synthesized in Hypothalamus Hormone Released into Posterior Pituitary Target of Posterior Pituitary AVP AVP Collecting duct, to  water permeability Oxytocin Oxytocin Uterus and breast T3 /T4 Hypothalamus ↓ release TRH ↓ portal circulation Anterior Pituitary ↓ stimulates Troph Cells TSH ↓ SYSTEMIC circulation Thyroid Gland ↓ stimulates T3 and T4 release T3 and T4 release controlled by –ve feed back at pituitary & hypothalamus T4 / T3 sites of action: – Cytosol (T4→ T3 conversion) Nucleus. ➔ major actions – Microsomes – Mitochondria % Change in Metabolic Rate T4 / T3 Biological affects ↑↑ Gluconeogenesis ↑ Glycogenolysis (liver) → ↑ plasma [glucose] ↑ Proteolysis → Muscle wasting ↑ Lipolysis → ↑ free fatty acids ↑ Na-K pump activity →↑ ATP usage → Heat generation ↑↑ Expression of β adrenoceptors → ↑ release and sensitivity to circulating catecholamines (adrenaline) PARAMETER HYPOTHYROID Basal metabolic rate ↓ Carbohydrate ↓ Gluconeogenesis metabolism ↓ Glycogenolysis Normal serum [glucose] Protein metabolism ↓ Synthesis ↓ Proteolysis Lipid metabolism Thermogenesis Autonomic nervous system ↓ Lipogenesis ↓ Lipolysis ↑ Serum [cholesterol] ↓ Normal levels of serum catecholamines HYPERTHYROID ↑ ↑ Gluconeogenesis ↑ Glycogenolysis Normal serum [glucose] ↑ Synthesis ↑ Proteolysis Muscle wasting ↑ Lipogenesis ↑ Lipolysis ↓Serum [cholesterol] ↑ ↑ Expression of β adrenoceptors (increased sensitivity to catecholamines, which remain at normal levels) Adrenal Medulla: Innervated by preganglionic sympathetic axons. Release Adrenaline & Nordrenaline – Increase respiratory rate. – Increase heart rate and cardiac output. ↑ serum Glucose – Constrict blood vessels, – Stimulate glycogenolysis. – Stimulate lipolysis. Adrenaline synthesis Tyrosine ↓ tyrosine hydroxylase L-dopa ↓ amino acid decarboxylase Dopamine ↓ catecholamine-H+ exchanger (VMAT1) Dense-core vesicles ↓ Dopamine β-hydroxylase Norepinephrine ↓ catecholamine-H+ exchanger (VMAT1) Norepinephrine ‘PNMT’ ↓ phenylethanolamine-N-methyltransferase Epinephrine. ↓ catecholamine-H+ exchanger (VMAT1) dense-core vesicles Key: confinement of PNMT to adrenal gland ➔ adrenaline produced by adrenals NOT nerves Adrenaline → inhibits insulin secretion → Stimulates glucagon secretion Amino acid - Recycling - Impact on metabolism (gluco/ketogenic) Synergies Neural & endocrine systems have synergistic interactions Neural system: - Sympathetic nervous system Endocrine system: - Adrenal (cortisol & adrenaline)system - Thyroid system. Adrenal + Sympathetic + Thyroid 1. ACTH stimulates the synthesis of dopa and norepinephrine. (more substrate) 2. Cortisol → up regulates PNMT (chromaffin cells) drives Noradrenaline →Adrenaline) synergy between the CRH-ACTH-cortisol axis and the sympathetic-epinephrine axis. STRESS sensed by the cortex - activates the CRH-ACTH-cortisol axis and amplifies epinephrine production. - ↑ Sympathetic Drive to the adrenal medulla) → ↑ Adrenaline release. - ↑ Thyroid levels → ↑ expression of Badrenoreceptors → ↑ response to Adrenaline