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

2. Obesity Trends* Among U.S. Adults BRFSS, 1985 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

3. Obesity Trends* Among U.S. Adults BRFSS, 1986 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

4. Obesity Trends* Among U.S. Adults BRFSS, 1987 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

5. Obesity Trends* Among U.S. Adults BRFSS, 1988 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

6. Obesity Trends* Among U.S. Adults BRFSS, 1989 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

7. Obesity Trends* Among U.S. Adults BRFSS, 1990 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

8. Obesity Trends* Among U.S. Adults BRFSS, 1991 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

9. Obesity Trends* Among U.S. Adults BRFSS, 1992 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

10. Obesity Trends* Among U.S. Adults BRFSS, 1993 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

11. Obesity Trends* Among U.S. Adults BRFSS, 1994 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

12. Obesity Trends* Among U.S. Adults BRFSS, 1995 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

13. Obesity Trends* Among U.S. Adults BRFSS, 1996 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

14. Obesity Trends* Among U.S. Adults BRFSS, 1997 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

15. Obesity Trends* Among U.S. Adults BRFSS, 1998 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

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

17. Obesity Trends* Among U.S. Adults BRFSS, 2000 Source: Mokdad A H, et al. J Am Med Assoc 1999;282:16, 2001;286:10.

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

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

20. 1985 2001

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

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

23. Alphabet Soup 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 TNFα Beta-Endorphin Dynorphin BDNF PYY IL-6 IL-1 IL-1RA Norepinephrine Amino Acids PRL-RL GAL-LP

24. Partial List of Systems Involved in Hypothalamic Control of Food Intake 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 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 CNS Regulatory Mechanisms Leptin, Insulin Caloric Intake Energy Balance Stored Calories Energy Balance Stored Calories

26. Leptin Receptor mRNA

27. Melanocortin System Ligands ACTH  -MSH POMC

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

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

30. Negative Energy Balance

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

32. Melanocortins

33. Positive Energy Balance

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

35. Involuntary Overfeeding--POMC

36. Involuntary Overfeeding

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

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

39. Agouti Related Peptide (AgRP)

46. Mechanisms of AgRP Action Irreversible MC receptor antagonism? 024 h48 h Food Off 2 Food On AgRPMTII

47. Mechanisms of AgRP Action

49. b

52. Model POMC Increased Weight Decreased Weight Leptin/Insulin R MC4 Receptor Y1 or Y5 Receptor Leptin Insulin WHITE FAT ArcuatePVN AgRP

53. Model AgRP POMC Increased Weight Decreased Weight MC4 Receptor Y1 or Y5 Receptor Leptin WHITE FAT ArcuatePVN Leptin Insulin Leptin/Insulin R

54. Model POMC Increased Weight Decreased Weight MC4 Receptor Y1 or Y5 Receptor Leptin WHITE FAT ArcuatePVN AgRP Leptin Insulin Leptin/Insulin R

55. Partial List of Systems Involved in Hypothalamic Control of Food Intake Leptin Insulin Amylin NPY CRH CHRL Urocortin Urocortin II Galanin Neurotensin CART Oxytocin  -MSH Corticosterone Serotonin Dopamine MCH Orexins Histamine Ghrelin GLP-1 GLP-2 AgRP Beacon Cannabinoids PRL-RL TNFalpha Beta-Endorphin Dynorphin BDNF IL-6 IL-1 IL-1RA NA-OMI Norepinephrine Amino Acids

56. Orexin-A MCH NPY AgRP Opioids Arcuate LHA Food Intake

57. Orexin-A MCH NPY AgRP Opioids Arcuate LHA Food Intake

58. AgRP and Opioids

60. Orexin-A MCH NPY AgRP Opioids Arcuate LHA Food Intake

63. Orexin-A MCH NPY AgRP Opioids Arcuate LHA Food Intake

64. Orexin and Opioids

67. MCH and Opioids

68. Orexin-A MCH NPY AgRP Opioids Arcuate LHA Food Intake Food Choice

69. AgRP & Low Fat Diet

70. AgRP & High Fat Diet

71. Orexin-A MCH NPY AgRP Opioids Arcuate LHA Food Intake Food Choice

72. Orexin and Food Choice

73. MCH and Food Choice

74. AgRP, Orexin and MCH

77. Orexin-A MCH NPY AgRP Opioids Arcuate LHA Food Intake Food Choice