Section VIII. Section VIII. Tissue metabolism Many tissues carry out specialized functions: Ch. 43 – look at different hormones affect metabolism of fuels, especially counter-insulin Ch. 44 – Proteins and cells of the blood Ch. 45 – Hemostasis and the clotting cascade

Chapt. 43 Ch. 43 hormone regulation Student Learning Outcomes: Describe the role of hormones in regulating fuel metabolism – appetite, absorption, transport, oxidation Explain the main functions of insulin Explain the role of glucagon Describe the role of epinephrine, cortisol, somatostatin, growth hormone and thyroid hormone Describe how these hormones exert control quickly by changes in phosphorylation state of enzyme, and more slowly by changes of gene expression

Table 1 Major hormones affecting fuel metabolism Glucose uptake Glucose output Glycogenolyis Anabolic Insulin ↑↑ ↓↓ ↓↓ Counterregulatory Glucagon - ↑↑ ↑↑ Epinephrine - ↑↑ ↑↑ initial Glucocorticoid ↓ ↑ - Growth hormone ↓ ↑ - Thyroid hormone - ↑ - Somatostatin - - -

Effects on fuel metabolism I. Insulin Insulin: Effects on fuel metabolism (Chapt. 26) Stimulates storage of glycogen in liver, muscle Stimulates synthesis of fatty acids and triagcylglyerols and storage in adipose tissue Stimulates synthesis in various tissues of >50 proteins There are insulinlike growth factors I and II (IGF-1, IGF-II) Paracrine action: release of insulin from b-cells suppresses secretion of glucagon from a-cells.

Glucagon II. Glucagon Major insulin counterregulatory hormone Produced as preglucagon in a-cells of pancreas 4 peptides in tandem: Glicentin-related peptide glucagon-related peptide 1 (GLP-1) glucagon-related peptide 2 (GLP-2) Proteolytic cleavage releases various combinations Different forms in different tissues Signals through G-protein-coupled receptor to cAMP and PKA

Somatostatin: (growth hormone release-inhibiting hormone) III. Somatostatin Somatostatin: (growth hormone release-inhibiting hormone) Preprosomatostatin is 116 aa Final cyclic 14-aa peptide (SS-14); From hypothalmus, also secreted d cells of pancreas In gut, prosomatostatin SS-28 (28-aa) form Inhibits release of many hormones: Growth hormone, TSH, insulin, glucagon, 5 receptors, G-protein receptor family – hormone activates inhibitory Ga; not stimulate cAMP Fig. 3

Growth hormone (somatotropin)stimulates growth: Made in somatotrophs of anterior pituitary Direct effects on targets, esp. liver, muscle GH receptors are cytosine tyrosine kinases (Janus) Indirect, induces insulinlike growth factors (IGF) Fig. 1

Control of secretion of growth hormone Control of secretion of GH: GHRH stimulates release GH-releasing hormone Binds receptors on somatotrophs Signals by cAMP, Ca2+-calmodulin GHRIH (somatostatin) inhibits release GH-release inhibiting hormone IGF-1 feedback from liver Insulinlike growth factor Plasma levels of fuels also control See also Table 2 list Fig. 2

GHRH stimulates release of growth hormone: Somatocrinin GHRH and GHRIH GHRH stimulates release of growth hormone: Somatocrinin 40-, 44-aa peptides Multiple signaling paths cAMP, Ca2+-calmodulin GHRIH inhibits release: Somatostatin Binds G-coupled receptors Inhibitory Ga Fig. 3

Anabolic effects of growth hormone Multiple anabolic effects of growth hormone: Broad effects on energy metabolism Uptake, oxidation of fuels Fig. 4

Production, activity of IGFs GH stimulates release of IGFs (liver) GH receptor is cytoplasmic tyrosine kinase type (Janus) IGFs are somatomedins Structure similar to insulin (insulinlike growth factors) IGF-1 70 aa; IGF-II 67 aa IGFs bind membrane RTKs Increase cell proliferation Fig. 5

III C. Epinephrine, norepinephrine Catecholamines epinephrine, norepinephrine Neurotransmitters or hormones Stress hormones increase fuel mobilization Tyrosine precursor Adrenergic receptors 9 different receptors: 6a, 3 b: b receptors work through G-protein coupled, adenylyl cyclase, cAMP, PKA a receptors G-protein coupled, PIP2-Ca2+ signal transcduction (Fig. 28.10) Different receptors on different tissues Mobilize fuels Fig. 26.13

Catecholamines (focus on epinephrine): Bioamines, stress hormones Also norepinephrine, dopamine Synthesis in adrenal medulla Act via a-adrenergic and b-adrenergic receptors (Ch. 26,28) Fig. 6: Epinephrine stimulates fuel metabolism, pancreatic endocrine function. Also stimulates glucagon release to reinforce effects; inhibit insulin

Cortisol is major Glucocorticooid: Neural and endocrine signals: Glucocorticoids (GC) Cortisol is major Glucocorticooid: ‘counterregulatory’, ↑blood glucose Neural and endocrine signals: Acetylcholine & serotonin: CRH = corticotropin-releasing hormone (midbrain) ACTH = adrenocorticotropic hormone Adrenal gland releases cortisol Cortisol does negative feedback (but overridden by stress) Fig. 7

Effects of Glucocorticoids (GC) Glucocorticoids (GC) have diverse effects: bind intracellular receptors, bind DNA, induce transcription of target genes Fuel metabolism effects often stimulate degradation Also nonmetabolic effects (Table 3) Fig. 8 fuel metabolic effects

Signal transduction by cortisol, intracellular receptors Cortisol and thyroid hormone bind intracellular receptors: Binding of hormone causes hormone- receptor complex to bind specific DNA sequences, increase transcription from target genes. Figs. 11.7,8

E. Thyroid hormone (TH) is derived from tyrosine: T3 and T4 made in thyroid acinar cells signal by binding intracellular nuclear receptors Fig. 9

Formation of thyroid hormone Formation of thyroid hormone (TH): Protein thyroglobulin secreted into colloid space Iodination, coupling Pinocytosis Digestion by lysosomes ~ 10:1 T4:T3 Synthesis stimulated by TSH in anterior pituitary TSH stimulates release T1/2 days in plasma Fig. 10

Regulation of TH levels TRH = thyrotropin-releasing hormone TSH = thyroid-stimulating hormone TSH binds membrane receptor, ↑cAMP Also through IP3 + DAG, Ca2+ T3 & T4 secreted from thyroid T3 inhibits release of TSH, TRH Fig. 11

Physiological effects thyroid hormone Normal TH affects fuel metabolism: Liver: carbohydrate, lipid metabolism Increase glycolysis, cholesterol synthesis Increase sensitivity of hepatocyte to gluconeogenic & glycogenolyticactions of epinephrine Adipocytes: sensitizes adipocyte to lipolytic action of epinephrine also increase availability of glucose to fat cells Muscle: increase glucose uptake, stimulate protein synthesis TH can increase heat production by stimulating ATP utilization in futile cycles (increase heat production by uncoupling)

F. GI hormones affect fuel metabolism Many GI hormones affect fuel metabolism: Direct and indirect effects: produced by many tissues (Table 4,5) GLP-1, glucagonlike peptide; GIP, Gastic inhibitory peptide CCK, cholecystokinin has indirect effects Fig. 12

Key concepts: Key concepts Insulin is major anabolic hormone Counterregulatory (counterinsulin) hormones include: Glucagon Somatostatin Growth hormone has diverse roles Catecholamine hormones Cortisol (glucacorticoid) promtoes survival Thyroid hormones secretion is highly regulated Intestines and stomach secrete hormones (incretins)

Review question Review question. 3. A dietary deficiency of iodine will lead to which of the following? A direct effect on the synthesis of thyroglobulin on ribosomes An increased secretion of thyroid-stimulatory hormone (TSH) Decreased production of thyrotropin-releasing hormone (TRH) Increased heat production Weight loss