1. MPB 333 The Molecular Endocrinology of Obesity and Diabetes Satiety and Hunger

2. Meal Patterning in Rodents

3. Behavioral Satiety Sequence in Rodents

4. Terminology Hunger Food Seeking Behavior Meal Initiation Meal Meal termination Satiety Satiate Nausea Inter-meal Interval Reward

5. Reward Pathways

6. Reward Pathways – Sensory Inputs

7. Lessons on Reward and Satiety from the Sham Feeding Model

8. Reward and Satiety

9. LH is Responsive to Oropharyngeal Sensory Inputs

10. Sensory-Specific Satiety

11. Brain Regions Implicated in Hunger and Satiety

13. Satiety Signals Gastric distension Gut peptides, hormones, and factors Ileal brake mechanism

14. Satiety Signals Most come from the GI tract. Secreted in response to food ingestion, create a sensation of fullness or satiety. Reduce meal size without causing malaise. Act within the time frame of a single meal Interact with other controllers of meal size.

15. Satiety Signals Reduce meal size comparably –In lean animals and –In genetically obese animals –In diet-induced obese animals Blocking their action leads to increased meal size. But…body weight not effected after repeated injections.

16. Assays for Proving Satiety Behavioral Satiety Sequence Aversive Conditioning

17. Anatomy of Hunger and Satiety Factors

18. Forebrain Hindbrain The effects of CCK and stomach stretch are integrated in vagal afferent fibers CCK Stretch Nodose Ganglion Vagus DOSE 30-Minute Food Intake

19. Gut-Brain Communication

21. Satiety and Hunger Factors

22. Cholecystokinin (CCK) - A well-characterized satiety factor acting on the NTS Ù Released from I cells in the duodenum in response to nutrients particularly fat and protein Ù Enters the blood, acts on gut motility, gallbladder contraction, and gastric and pancreatic enzyme secretion Ù Diffuses locally to activate CCK-A receptors present on the vagal snsory nerves Ù Reduces food intake in the short-term

23. PYY: a Gut Peptide Released in Response to Short Chain Fatty Acids Cherbut et al., Short-chain fatty acids modify motility through nerves and polypeptide YY release. Am. J. Physiol. 275, G1415-G1422, 1998 Ilial Infusion 50mM SCFA

24. Effect of CCK on Food Intake

25. Effects of Leptin

26. Vagotomy blocks inhibition of food intake by CCK

27. Discovery of a Novel Satiety Factor: PYY 3-36

28. PYY3-36 inhibits feeding under carefully controlled conditions

29. PYY 3-36 Inhibits Food Intake in MC4-R -/- Mice

30. PYY 3-36 Inhibits Food Intake in Vagotomized Mice Control: Vagotomy blocks inhibition of food intake by CCK

31. PYY 3-36 Inhibits Firing of Anorexigenic POMC Neurons

32. PYY 3-36 Activates AP Neurons

33. A Conditioned-Taste Aversion Assay for PYY 3-36

34. PYY 3-36 Exhibits Aversive Activity

35. Other Satiety Factors Amylin Preproglucagon-derived peptides PYY Apo A-IV Bombesin

36. Meal Initiation 1.Glucostatic Theory 2. Gastric Pressure Receptors 3. Ghrelin

37. Glucostatic Theory

38. Ghrelin: a meal initiation factor acting at the GHS-R From: Cummings, D.E. et al. Diabetes 50, 1714-1719, 2001

39. Ghrelin Increases Hunger and Food Intake in Humans Wren, et al. JCEM. 86(12):5992-5, 2001.

40. Ghrelin Levels Rise With Weight Loss Cumming, et al. NEJM. 2002 346:1623-30.

41. Ghrelin Acts on Vagal and Hypothalamic Neurons to Stimulate Food Intake

43. The Big Picture

44. Leptin Tonically Regulates a Multitude of Circuits Involved in Acute Intake and Expenditure Behavioral Endocrine Autonomic

45. Regulation of CCK Response by Leptin

46. Synergy by CCK and Leptin to Inhibit Food Intake Matson and Ritter. AJP. 45:R1038-45, 1999. SalineCCKLeptinCCK + Leptin 10 0 20 30 40 48-hour chow Intake (g) b a

47. Leptin Regulates the Responsiveness of Vagal Afferent Nerves to CCK

48. MC4-R impacts autonomic, endocrine, and behavioral effector pathways to balance energy intake and expenditure so as to maintain energy homeostasis. The melanocortin system is an ideal neuroanatomical substrate for the integration of long-term and short-term energy needs – a second pathway for tonic effects of leptin on satiety

49. Activation of c-Fos by CCK by in POMC NTS Neurons

50. MC4-R Blockade Inhibits CCK Action

51. Feeding-activated c-Fos in POMC NTS Neurons

52. A Majority of NTS POMC Neurons are Leptin- Responsive