Chapter 23, Hormonal Regulation and Integration of Mammalian Metabolism

1. Dr. Zengyi Chang’s Lecture notes for Dec. 26, 2007 (Biochemistry II) Chapter 23, Hormonal Regulation and Integration of Mammalian Metabolism ★Specialized metabolism of major organs and tissues: the division of labor; ★Coordination of metabolism for different organs via hormones. ★ Responding to changing external conditions. ★ Meeting the demands of growth and reproduction.

2. Each organ has a specialized function: The division of labor. Issues:which fuels they use, which fuels they generate, how they adjust their metabolism at different physiological conditions

3. GLUT2 Metabolism of sugars in Liver. Glucokinase (Km =10mM) Blood Glc (4 mM) (then transported to other tissues) Fatty acids are the preferred fuel for energy production in heptocytes. Occurs when the carbohydrate intake is in excess.

4. Metabolism of amino acids in liver. Glucose-Alanine cycle smoothes out fluctuations of blood glucose level during meals.

5. Metabolism of fatty acids in liver.

6. Excess carbohydrates are converted into lipids in liver and transported to adipose tissue for storage. Adipose tissue stores and supplies fatty acids Stored triacylglycerols are converted into fatty acids when in need by other tissues (epinephrine carries the message).

7. Muscle is a consumer of fatty acids, ketone bodies and glucose. Muscles lack glucose 6-phosphatase. Phosphorylated Glc Fermentation Aerobic oxidation

8. Metabolic cooperation between the skeletal muscle and liver. The Cori Cycle

9. Mitochondria make up about half of the volume of the heart Muscle cells. The heart completely depends on aerobic oxidation to obtain energy, i.e., O2 is absolutely needed for heart to work!

10. Brain is a major glucose consumer The most fastidious, one of the most voracious of all the organs! O2 and glucose cannot be interrupted! Fatty acids do not serve as a fuel! Consumes about 120 g glucose daily.

11. Blood mediates the metabolic interactions among all tissues. Blood

12. Metabolism is regulated at different levels • At the level of the individual cells: • Regulation of enzyme activities by substrate availability, allosteric mechanisms, covalent modifications. • At the level of the whole organism: • Chemical messengers of the neuroendocrine system, neurotransmitters and hormones.

13. Coordination of metabolism in separate organs is achieved by the neuroendocrine system. Over short distance Over long distance

14. Fuel metabolism of different organs is coordinated through various hormones • Insulin, glucagon, and epinepherine have been found to interplay in coordinating fuel metabolism in muscle, liver, and adipose tissue, thus keeping the blood glucose level near 4.5 mM. • Insulin signals high blood glucose (acts mainly on liver, muscle and adipose tissues). • Glucagon signals low blood glucose (acts mainly on liver and adipose tissues). • Epinepherine signals impending activity (acts on muscle, liver and adipose tissues).

15. The well-fed state: Insulin stimulates glucose consumption and storage in muscle and liver. Stimulated by an increase in blood glucose level. Stored as glycogen or triacyglycerol.

16. The fasting state: Glucagon stimulates glucose production and release in liver. Also mobilizes the fatty acids (sparing glucose for the brain)

17. In untreated diabetes, insulin is either not produced (Type I or IDDM) or is not recognized by the tissues (Type II or NIDDM), and the uptake of blood glucose is compromised.High level of glucose in blood and urine; production and excretion of ketone bodies.

18. Active fatty acid mobilization Active synthesis of ketone bodies. Active protein degradation. Fuel metabolism in liver during prolonged fasting or uncontrolled diabetes mellitus. Active gluconeogenesis

19. Hormones are chemical messengers secreted by certain tissues into the blood or institial fluid, serving to regulate the activity of other tissues.

20. Hormones, extremely potent, are often present in extremely low concentrations and a bioassay must be established before their discovery and characterization. • For instance, insulin was discovered as a substance affecting the volume and composition of urine produced by a dog (Banting, Macleod and Collip, 1920s).

21. The Nobel Prize in Physiology or Medicine 1923 "for the discovery of insulin" Frederick Grant Banting John James Richard Macleod b. 1891d. 1941 b. 1876(in Cluny, Scotland)d. 1935

22. Radioimmunoassya (RIA) was an extremely sensitive quantitative method developed to assay peptide hormones (Yalow, 1970s) • Antibodies binding to a hormone specifically and with high affinity are used. • A constant amount of antibody is incubated with a fixed amount of radioactively labeled hormone. • Unlabeled hormone in samples will compete with the labeled ones to bind to the antibodies.

23. The amount of the unlabeled is revealed by measuring the amount of the labeled that disappears. The principle of the radioimmunoassay (RIA) The amount of labeled hormone bound will reflects the concentration of unlabeled hormone present (usually as a sample of blood or tissue extract) .

24. The Nobel Prize in Physiology or Medicine 1977 "for their discoveries concerning the peptide hormone production of the brain" “For her development of radioimmunoassays of peptide hormones.” Roger Guillemin Andrew V. Schally Rosalyn Yalow

25. Hormones are chemically diverse

26. Peptide hormones are usually generated as larger precursors.

27. Insulin is made from preproinsulin via proteolytic processing.

28. POMC (in hypothalamus) Multiple peptide hormones can be derived from one prehormone polypeptide.

29. Two of the general mechanisms for hormone action.

30. There is a hierarchical chain of command in hormonal signaling. Coordination center of the endocrine system. Via direct neuronal connection

31. The hormonal cascades result in large amplification of the initial signal.

32. The adipose tissue was found to produce a protein hormone, leptin, that act on the hypothalamus to regulate the feeding behavior and energy expenditure of a mammal to maintain a constant body mass (homeostasis). A defect in leptin production leads to obesity!

33. A set-point model for maintaining a constant body mass Leptin (1994)

34. Summary • Each organ/tissue in a mammal has specialized roles in metabolism. • Liver has remarkable metabolic flexibility and works for other tissues in providing appropriate fuels. • The working of all organs/tissues is highly coordinated/integrated via the hormones, a group of chemically diverse molecules.