CHAPTER 23 Hormonal Regulation and Integration of Mammalian Metabolism

1. CHAPTER 23Hormonal Regulation and Integration of Mammalian Metabolism 23.1 Hormones: Diverse Structures for Diverse Functions 23.2 Tissue-Specific Metabolism: The Division of Labor 23.3 Hormonal Regulation of Fuel Metabolism 23.4 Obesity and the Regulation of Body Mass 23.5 Obesity, the Metabolic Syndrome, and Type 2 Diabetes

2. Metabolism at the Organism Level • Previously focused on metabolism at the cell and molecular level • Role and mechanism of specific enzymes • Flux of metabolites through pathways • Feedback regulation of metabolic pathways • Transport of metabolites across organelle membranes • Here focus on metabolism at the whole organism level • Role and structure of specific tissues and organs • Flux of metabolites from organ to organ • Hormonal regulation of metabolism • Control of body mass

3. Cell Signaling • In Synaptic (neuronal) signaling, nerve cells release neurotransmitters that to a synaptic junction • Propagation of nerve signals • Control of muscle contraction • Stimulation of endocrine cells • Paracrine signals affect nearby cells • Endocrine signals affect the whole system • Stimulation of glycogen breakdown • Stimulation of growth and differentiations • Regulation of water retention by kidneys

4. Radioimmunoassay (RIA)

5. Hormone classes • Peptides, Catecholamines, Eicosanoid - cell surface Receptors • Steroid, Vitamin D, Retinoid, Thyroid traverse the membrane

6. Mechanism of Action of Signaling Molecules • Both neurotransmitters and hormones act via binding to specific protein targets called receptors • Each hormone has its own receptor; each receptor elicits physiological response upon binding to its natural ligand • Typically, only cells that should receive the signal express the receptors for this specific signaling molecule • Most receptors are membrane-bound proteins; their mechanism of action was covered under “Bio-signaling” • Some receptors are soluble proteins that modulate the expression of genes; these are called “nuclear receptors”

8. Peptide Hormone Insulin • A small protein (or a large peptide) hormone • Made at islets of Langerhans in pancreas • Synthesized on ribosome of -cells as preproinsulin and processed into the 5.8 kDa active form • Stored in secretory vesicles in -cells • Secreted in response to increased blood glucose levels • Binds to insulin receptors in muscle, brain, liver, adipose tissue, and other fuel-metabolizing tissues • In muscle, insulin facilitates glucose uptake • In liver, insulin promotes glycogen synthesis • In adipocytes, insulin promotes glycerol synthesis and inhibits breakdown of fats

10. Catecholamines

11. Eicosanoids

12. Steroids

13. Vitamin D

14. Retinoid

15. Thyroid Hormones

16. The Major Endocrine Glands

17. The Major Endocrine Systems and Their Targets

18. Hypothalamus is the Coordination Center of the Endocrine System • Hypothalamus is a small region of the forebrain in animals with skulls • It receives and integrates nerve signals from the central nervous system • It synthesizes small peptide hormones oxytocin and vasopressin • It synthesizes several releasing factors that act regulate the function of anterior pituitary

19. Pituitary Releases of Hormones that Target Other Hormonal Glands • Posterior pituitary (neurohypophysis) is a collection of hypothalamic axons that carry and release hormones that were made in the hypothalamus • Anterior pituitary (adenohypophysis) is endocrine organ that receives releasing factors from hypothalamus via blood vessels

20. Hypothalamus-Pituitary System • Anterior pituitary hormones are synthesized in pituitary gland and released in response to a hormone-specific releasing factors • Posterior pituitary hormones are synthesized in neurons of hypo-thalamus and secretedinto bloodin response to neuronal signals

21. Posterior Pituitary Hormones Oxytocin and Vasopressin • Oxytocin promotes • contraction of smooth muscle of the uterus during labor • milk release from the mammary gland • Vasopressin promotes • water readsorption in kidneys to maintain balance of salts in the body • constriction of blood vessels and increases blood pressure • Both hormones • play roles is social behavior such as pair bonding; these CNS effects do not involve pituitary secretion

22. Cortisol Release Cascade

23. 23.2 Tissue-Specific Metabolism: The Division of Labor • Liver process and distributes nutrients • Sugars, Amino Acids, Lipids • Adipose Tissue Stores and supplies Fatty acids • Brown Adipose Tissue is thermogenic • Muscles use ATP for mechanical work • Brain Uses energy for electrical impulses • Blood carries O2 metabolites and hormones

25. Liver: G6P

26. Liver: AAs

27. Liver: Fatty Acids

28. Adipocytes of white and brown adipose tissue

29. Muscle: fueling, regimes

30. The fuels that supply ATP in the brain.

31. The Endocrine System of the Pancreas

32. Regulation of Insulin Production in beta-cells • 1. Glucose import • 2. K channels close • 3. Ca influx • 4 Hi Ca activates insulin release

33. ATP-Gated K+ Channels in -cells • Increased glucose in -cells leads to increased concentration of ATP • Binding of ATP closes the K+ channels and depolarizes the membrane • Sulfonylurea drugs close channels and stimulate insulin release

35. Lipogenic Liver after a Calorie-Rich Meal • Stores excess glucose as glycogen • Converts excess glucose into fatty acids

36. Glucogenic Liver during Fasting • Converts glycogen and pyruvate into glucose • Converts fatty acids into ketone bodies

37. fasting or diabetes mellitus

38. Physiology and Blood Glucose Levels • Blood glucose is normally determined after several hours of fasting • High fasting blood glucose level (126 or higher) is a warning sign for diabetes • Lowfastingglucose levels below 50 (in men) or 40 are warning signs of various hypoglycemic conditions • Blood glucose levels after meal (postprandial) are typically higher (up to 145 mg / 100 mL is normal)

39. Diabetes Mellitus • Impaired insulin signaling leads to abnormally high blood glucose levels • In adults, two types of diabetes can be distinguished • Type 1: Insulin deficiency, usually due to the destruction of -cells • Type 2: Insulin resistance, usually due to defective insulin receptors • Treatments for the two types are different • Type 1: Administer insulin when blood glucose is raising • Type 2: Weight loss and increased physical activity are likely to offer cure as long as insulin secretion from pancreas is normal • High blood glucose increases risk of cardiovascular disease, renal failure, and damage to small blood vessels and nerves • Molecular mechanism of damage often involves glycosylation of proteins

40. Treatments for Type-2 Diabetes Mellitus • Large studies from 2008 suggest that control of blood glucose with medications reduces the risk of kidney damage but has little effect on cardiovascular disease • Pooled analysis of 42 controlled clinical trials suggested that Avandia patientsface 30-40% greater risk of heart attack; the drug carries a black-box warning now

42. Leptin and Control of Body Mass • Leptin signals to the brain that the body does not need any more food

43. Hypothalamic Regulation of Food Intake • Beta 3 Adrenergic Receptor

44. Hormones that Control Eating

45. JAK-STAT mechanism of leptin signal transduction

46. Possible mechanism for cross-talk