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Section VIII.

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.

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Section VIII.

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  1. 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

  2. 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

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

  4. 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.

  5. II. Glucagon • Glucagon • Major insulin counterregulatory hormone • Produced as preglucagon in a-cells of pancreas • 4 peptides in tandem: Glicentin-related peptide Glucagon 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

  6. 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

  7. Growth hormone • 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

  8. 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

  9. 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

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

  11. 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

  12. 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

  13. Epinephrine • 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

  14. 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

  15. 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

  16. 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

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

  18. 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

  19. Regulation of TH levels • 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

  20. 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)

  21. 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

  22. 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)

  23. 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

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