1. MISS 2011 Physiology of Weight Regulation: Implications for Bariatric Surgery Lee M. Kaplan, MD, PhD Gastrointestinal Unit MGH Weight Center LMKaplan@partners.org February 24, 2011

2. Obesity Historical view Lifestyle choice Characterological flaw (willpower, psychology) Current perspective Complex physiology Epidemic from changes in modern environment Widely recognized as a disease Huge burden of associated illness – a cause of more than 60 medical disorders (incl. 12 types of cancer) Devastating effect on efficacy and quality of life

3. Feedback Regulation of Energy Metabolism Adiposetissue Adipocytokines (esp. leptin) CNS Food intake Nutrient handling Energy expenditure LiverMuscleBone Metabolic needs Sensory Organs GI Tract EnvironmentalsensingEnergystores

4. Interaction of Weight and Satiety Pathways

5. Defense of a Body Fat “Set Point” Forced dietary manipulation Ad libitum fed Adapted from S. Woods

6. Obesity: A Failure of Weight Regulation Genetics Developmental programming Environment Adipose tissue Leptin HT Food intake Energy expenditure Nutrient handling Cortex GI Tract

7. Defense of a Body Fat “Set Point” 20253035 Body Mass Index (kg/m 2 ) kcal / 24 hours 2000 2500 3000 EnergyExpenditureEnergyIntake (–) Energy Balance (+) Energy Balance Adapted from Weigle, 1995

8. Weight Loss Surgery Combination Roux-en-Y Gastric Bypass Adjustable Gastric Banding Vertical Sleeve Gastrectomy Gastric

9. Why is gastric bypass so effective?

10. Mechanisms of Bariatric Surgery Restricted food intake Malabsorption Classical model: Mechanical Altered GI signals to brain Endocrine Neuronal Altered GI signals to other tissues (pancreas, liver) Current model: Physiological

11. Signaling Changes after Gastric Bypass Distal signals Exposure of distal small bowel to undigested food Elevated PYY Elevated GLP-1 Proximal signals Proximal gastric distension Diminished ghrelin Distal gastric exclusion Duodenal exclusion Altered portal venous sensing

12. Roux-en-Y Gastric Bypass in Mice Roux: 10-15% of total intestinal length BP: 10-15% of total intestinal length Common : >70% of total intestinal length GP DS

13. RYGB Induces Weight Loss in Mice Stylopoulos et al., 2009

14. Potential Physiologic Mechanisms Appetitive drive/food intake Nutrient absorption Energy expenditure

15. RYGB Reduces Nutrient Intake Cumulative Food Intake (kcal) Stylopoulos et al., 2009

16. Nutrient Absorption (%) Before RYGB RYGB Does Not Alter Caloric Absorption After RYGB Stool Calorimetry Stylopoulos et al., 2009

17. RYGB Alters Diet Preferences

18. GI Endocrine Responses to RYGB GLP-1 PYYAmylin GhrelinGIP Shin et al., 2010

19. GLP-1 Signaling Is Not Required for Improved Insulin Sensitivity after RYGB Munoz and Kaplan, unpublished

20. GLP-1 Signaling Required for Improved OGT C57BL/6 DIO Mice 6 week GLP-1 receptor antagonism Munoz and Kaplan, unpublished

21. GBP Increases Energy Expenditure Stylopoulos et al., 2009

22. RYGB Increases Energy Expenditure TEE - VO 2 (ml/hr/kg.75 ) REE - VO 2 (ml/hr/kg.75 ) ShamRYGBWeight-matched * p<0.05 ** p<0.001 ** * * Stylopoulos et al., 2009

23. Surgery is the Un-Diet DietSurgery Appetite   Hunger  Satiety   Reward-based eating  Energy expenditure  Stress response 

24. Appetite Energy balance Glucose metabolism RYGB - Physiologic Model Central Mechanisms Gastric Bypass Gut hormones Efferent neurons Improved Diabetes Weight Loss Liver Pancreas

25. Altering the “Set Point” with Gastric Surgery 30354045 Body Mass Index (kg/m 2 ) kcal / 24 hours 2000 2500 3000 Baseline Energy Expenditure Baseline Energy Intake Post-op Energy Intake Post-op Energy Expenditure

26. RYGB: Resolution of the “Overfed” State 30354045 Body Mass Index (kg/m 2 ) kcal / 24 hours 2000 2500 3000 Post-op Energy Intake Post-op Energy Expenditure Overfed state

27. Set Point and Weight Regain Fat Mass Set Point Time (years) Aging and environmental influences Surgery Environmental influences and aging

28. Summary RYGB works by influencing the normal physiological regulation of energy balance and glucose homeostasis alters appetitive drives and decreases food intake Increases diet-induced thermogenesis There are multiple types of surgery with distinct and overlapping mechanisms of action RYGB influences glucose homeostasis through decreased food intake, decreased body fat and direct effects independent of the other two Alters regulation of both insulin sensitivity and pancreatic  -cell function Effects of gastric banding mediated by weight loss alone

29. Summary There are GI anatomic correlates of outcome stomach for food intake regulation small bowel for regulation of energy expenditure, glucose homeostasis GLP-1 and MC4R have essential roles in the signaling mechanisms underlying response to surgery GLP-1 role appears limited to glucose homeostasis Roles of PYY, CCK, ghrelin, amylin, glucagon, OXM not clear The widespread physiological effects of surgery suggest many undiscovered molecular mechanisms

30. S mall A nimal M etabolic S urgery Core Resource PROGRAM ANNOUNCEMENT The Physiology of Metabolic Surgery: Lessons from Animal Models The Second International Workshop on Animal Models of Weight Loss Surgery April 3-5, 2011 ● Boston, Massachusetts Register at: www. amw11. org HARVARD MEDICAL SCHOOL BOSTON NUTRITION / OBESITY RESEARCH CENTER

31. S mall A nimal M etabolic S urgery Core Resource The Physiology of Metabolic Surgery: Lessons from Animal Models April 3-5, 2011 ● Boston, Massachusetts Register at: www. amw11. org Program Surgical overview Physiological effects of weight loss surgery Effects on food intake and appetitive behavior Effects on energy expenditure Effects on glucose homeostasis GI mechanisms CNS mechanisms Medical device solutions and physiology Genetic contributions and systems biology Live surgical demonstrations