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

MPB 333 The Molecular Endocrinology of Obesity and Diabetes Satiety and Hunger. Meal Patterning in Rodents. Behavioral Satiety Sequence in Rodents. Terminology Hunger Food Seeking Behavior Meal Initiation Meal Meal termination Satiety Satiate Nausea Inter-meal Interval Reward. Reward Pathways.

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

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  1. MPB 333 The Molecular Endocrinology of Obesity and DiabetesSatiety and Hunger

  2. Meal Patterningin Rodents

  3. Behavioral Satiety Sequencein Rodents

  4. TerminologyHungerFood Seeking BehaviorMeal InitiationMealMeal terminationSatietySatiateNauseaInter-meal IntervalReward

  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

  12. 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. 30-Minute Food Intake DOSE The effects of CCK and stomach stretch are integrated in vagal afferent fibers Forebrain Hindbrain Stretch CCK Vagus Nodose Ganglion

  19. Gut-Brain Communication

  20. Gut-Brain Communication

  21. Satiety and Hunger Factors

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

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

  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: PYY3-36

  28. PYY3-36 inhibits feeding under carefully controlled conditions

  29. PYY3-36 Inhibits Food Intake in MC4-R-/- Mice

  30. PYY3-36 Inhibits Food Intake in Vagotomized Mice Control: Vagotomy blocks inhibition of food intake by CCK

  31. PYY3-36 Inhibits Firing of Anorexigenic POMC Neurons

  32. PYY3-36 Activates AP Neurons

  33. A Conditioned-Taste Aversion Assay for PYY3-36

  34. PYY3-36 Exhibits Aversive Activity

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

  36. Meal Initiation1.Glucostatic Theory2. Gastric Pressure Receptors3. 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 HumansWren, et al. JCEM. 86(12):5992-5, 2001.

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

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

  42. 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 ExpenditureBehavioralEndocrineAutonomic

  45. Regulation of CCK Response by Leptin

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

  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

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