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The regulation of appetite

The regulation of appetite. Randy J. Seeley Department of Psychiatry University of Cincinnati. Obesity Trends* Among U.S. Adults BRFSS, 1985. Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10. Obesity Trends* Among U.S. Adults BRFSS, 1986.

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The regulation of appetite

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  1. The regulation of appetite Randy J. Seeley Department of Psychiatry University of Cincinnati

  2. Obesity Trends* Among U.S. AdultsBRFSS, 1985 Source: Mokdad A H, et al. J Am Med Assoc1999;282:16, 2001;286:10.

  3. Obesity Trends* Among U.S. AdultsBRFSS, 1986 Source: Mokdad A H, et al. J Am Med Assoc1999;282:16, 2001;286:10.

  4. Obesity Trends* Among U.S. AdultsBRFSS, 1987 Source: Mokdad A H, et al. J Am Med Assoc1999;282:16, 2001;286:10.

  5. Obesity Trends* Among U.S. AdultsBRFSS, 1988 Source: Mokdad A H, et al. J Am Med Assoc1999;282:16, 2001;286:10.

  6. Obesity Trends* Among U.S. AdultsBRFSS, 1989 Source: Mokdad A H, et al. J Am Med Assoc1999;282:16, 2001;286:10.

  7. Obesity Trends* Among U.S. AdultsBRFSS, 1990 Source: Mokdad A H, et al. J Am Med Assoc1999;282:16, 2001;286:10.

  8. Obesity Trends* Among U.S. AdultsBRFSS, 1991 Source: Mokdad A H, et al. J Am Med Assoc1999;282:16, 2001;286:10.

  9. Obesity Trends* Among U.S. AdultsBRFSS, 1992 Source: Mokdad A H, et al. J Am Med Assoc1999;282:16, 2001;286:10.

  10. Obesity Trends* Among U.S. AdultsBRFSS, 1993 Source: Mokdad A H, et al. J Am Med Assoc1999;282:16, 2001;286:10.

  11. Obesity Trends* Among U.S. AdultsBRFSS, 1994 Source: Mokdad A H, et al. J Am Med Assoc1999;282:16, 2001;286:10.

  12. Obesity Trends* Among U.S. AdultsBRFSS, 1995 Source: Mokdad A H, et al. J Am Med Assoc1999;282:16, 2001;286:10.

  13. Obesity Trends* Among U.S. AdultsBRFSS, 1996 Source: Mokdad A H, et al. J Am Med Assoc1999;282:16, 2001;286:10.

  14. Obesity Trends* Among U.S. AdultsBRFSS, 1997 Source: Mokdad A H, et al. J Am Med Assoc1999;282:16, 2001;286:10.

  15. Obesity Trends* Among U.S. AdultsBRFSS, 1998 Source: Mokdad A H, et al. J Am Med Assoc1999;282:16, 2001;286:10.

  16. Obesity Trends* Among U.S. AdultsBRFSS, 1999 Source: Mokdad A H, et al. J Am Med Assoc1999;282:16, 2001;286:10.

  17. Obesity Trends* Among U.S. AdultsBRFSS, 2000 Source: Mokdad A H, et al. J Am Med Assoc1999;282:16, 2001;286:10.

  18. Obesity Trends* Among U.S. AdultsBRFSS, 2001 Source: Mokdad A H, et al. J Am Med Assoc1999;282:16, 2001;286:10.

  19. Accuracy! Energy Intake in a Year 912500 calories Error of 0.4% Or 11 calories/day Gaining 1 pound (0.45 kg) in a year 4050 calories

  20. 1985 2001

  21. Humoral Regulation CNS Regulatory Mechanisms Caloric Intake Adiposity Signals Energy Balance Stored Calories

  22. Humoral Regulation CNS Regulatory Mechanisms Caloric Intake Leptin, Insulin Energy Balance Stored Calories

  23. Leptin Insulin Amylin NPY CRH UCN UCN II Galanin Neurotensin CART Oxytocin -MSH Corticosterone Serotonin Dopamine MCH Orexins Histamine Ghrelin GLP-1 GLP-2 AgRP Beacon Cannabinoids Alphabet Soup • TNFα • Beta-Endorphin • Dynorphin • BDNF • PYY • IL-6 • IL-1 • IL-1RA • Norepinephrine • Amino Acids • PRL-RL • GAL-LP

  24. Leptin Insulin Amylin NPY CRH Urocortin Urocortin II Galanin Neurotensin CART Oxytocin -MSH Corticosterone Serotonin Dopamine MCH Orexins Histamine Ghrelin GLP-1 GLP-2 AgRP Beacon Cannabinoids Partial List of Systems Involved in Hypothalamic Control of Food Intake • TNFalpha • Beta-Endorphin • Dynorphin • IL-6 • IL-1 • IL-1RA • Norepinephrine • Amino Acids • PRL-RL “Abandon all hope, ye who enter here.” Dante’s Inferno

  25. Humoral Regulation CNS Regulatory Mechanisms Caloric Intake Leptin, Insulin Energy Balance Stored Calories

  26. Leptin Receptor mRNA

  27. Ligands ACTH -MSH POMC Melanocortin System

  28. Ligands ACTH -MSH Receptors MC1 (skin and hair) MC2 (adrenal) MC3 (hypothalamus) MC4 (CNS) POMC Melanocortin System Crawford et al., 1996

  29. Ligands ACTH -MSH AgRP Receptors MC1 (skin and hair) MC2 (adrenal) MC3 (hypothalamus) MC4 (CNS) POMC Melanocortin System

  30. Negative Energy Balance

  31. A “Simple” Model Energy Balance Negative Low Leptin, Insulin - + AgRP POMC Increased Food Intake and Weight Gain

  32. Melanocortins

  33. Positive Energy Balance

  34. A “Simple” Model Energy Balance Negative Positive Low Leptin, Insulin High Leptin, Insulin + + - - POMC AgRP POMC AgRP Increased Food Intake and Weight Gain Decreased Food Intake and Weight Loss

  35. Involuntary Overfeeding--POMC

  36. Involuntary Overfeeding

  37. POMC/-MSH/MC4 • Critical to the response to positive energy balance • Integrates many inputs including feedback hormones such as leptin and insulin

  38. Ligands ACTH -MSH AgRP Receptors MC1 (skin and hair) MC2 (adrenal) MC3 (hypothalamus) MC4 (CNS) POMC Melanocortin System

  39. Agouti Related Peptide (AgRP)

  40. Agouti Related Peptide (AgRP)

  41. 70 60 Saline 1nm AgRP 50 *** *** 24-h Food Intake (g) 40 *** *** * 30 20 10 0 24 48 72 120 144 Hours Agouti Related Peptide (AgRP)

  42. 70 60 Saline 1nm AgRP 50 *** *** 24-h Food Intake (g) 40 *** *** * 30 20 10 0 24 48 72 120 144 Hours Agouti Related Peptide (AgRP)

  43. 70 60 Saline 1nm AgRP 50 *** *** 24-h Food Intake (g) 40 *** *** * 30 20 10 0 24 48 72 120 144 Hours Agouti Related Peptide (AgRP)

  44. 70 60 Saline 1nm AgRP 50 *** *** 24-h Food Intake (g) 40 *** *** * 30 20 10 0 24 48 72 120 144 Hours Agouti Related Peptide (AgRP)

  45. 70 60 Saline 1nm AgRP 50 *** *** 24-h Food Intake (g) 40 *** *** * 30 20 10 0 24 48 72 120 144 Hours Agouti Related Peptide (AgRP)

  46. Mechanisms of AgRP Action Irreversible MC receptor antagonism? AgRP MTII -1 0 2 24 h 48 h Food Off Food On

  47. Mechanisms of AgRP Action

  48. Mechanisms of AgRP Action

  49. Mechanisms of AgRP Action b

  50. Mechanisms of AgRP Action

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