Why is Bariatric Surgery so Effective?
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Bariatric surgery leads to long-term weight loss and improved health outcomes through physiological rather than mechanical mechanisms. It alters gastrointestinal signals that change the body's defended fat mass set point and regulate appetite and metabolism. Specifically, surgery modifies the luminal environment and gut microbiota composition, increasing circulating bile acids and triggering hormonal and neuronal signals that decrease hunger and food reward while increasing energy expenditure. This physiological reprogramming opposes the effects of dieting and underlies the durable benefits of bariatric procedures.
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Why is Bariatric Surgery so Effective?
- 1. Obesity Series 2020 Lee Kaplan, MD, PhD, FTOS Director Obesity, Metabolism, and Nutrition Institute Massachusetts General Hospital Why is Bariatric Surgery So Effective?
- 2. Obesity Series 2020 Dr. Lee Kaplan discusses the role of the gastrointestinal tract and gut microbiota in the mechanism of action of bariatric surgery. Why is Bariatric Surgery So Effective?
- 3. MASSACHUSETTS GENERAL HOSPITAL MASSACHUSETTS GENERAL HOSPITAL Why is Bariatric Surgery So Effective? Lee M. Kaplan, MD, PhD Obesity, Metabolism and Nutrition Institute Massachusetts General Hospital LMKaplan@mgh.harvard.edu December 2, 2020 Fernando Botero, 1932-
- 4. MASSACHUSETTS GENERAL HOSPITAL Defense of a physiologically determined weight and fat mass Forced dietary manipulation Ad libitum fed Woods SC et al., 1989
- 5. MASSACHUSETTS GENERAL HOSPITAL Classic weight graph after calorie restriction Svetky, et al. JAMA. 2008. PMID: 18334689 Phase 1 Acute WL Phase 2 “Weight Maintenance” Phase 2 Intervention
- 6. MASSACHUSETTS GENERAL HOSPITAL Body fat mass is a physiologically-regulated phenotype • At multiple stages during development • Loss of baby fat • Fat changes with puberty • Fat changes with aging • Fat changes with menopause • During and after pregnancy • Before and after hibernation • Before and after long-distance migration (birds, butterflies) Obesity results from inappropriate (pathophysiological) regulation of body fat mass
- 7. MASSACHUSETTS GENERAL HOSPITAL At most times, the body seeks a stable fat mass Liver Similar to other regulated tissues Red blood cells Physical tissue removal (resection or phlebotomy) leads to rapid regrowth
- 8. MASSACHUSETTS GENERAL HOSPITAL Human weight perturbation protocol Leibel et al., NEJM 1995;335:521 Percent of Initial Weight Time 120 − 110 − 100 − 90 − 80 − 70 − wt initial wt −10 wt −20 wt +10 Studies Energy Expenditure Energy Intake Neuroendocrine Axes Autonomic Physiology Muscle Physiology Brain Imaging Dietary Restriction / Overfeeding (No Change in Fat Mass Set Point)
- 9. MASSACHUSETTS GENERAL HOSPITAL Fat Mass Set Point Normal Obesity Decreased appetitive drive Increased thermogenesis Increased appetitive drive Decreased thermogenesis There must be physiological programs to drive and coordinate these effects Relationship to set point drives physiological response more than set point itself
- 10. MASSACHUSETTS GENERAL HOSPITAL What this means … Obesity results from a dysfunction of the normal fat mass regulatory mechanisms … … leading to an elevated defended body fat mass
- 11. MASSACHUSETTS GENERAL HOSPITAL What it also means … Overeating does not cause obesity … … obesity causes overeating
- 12. MASSACHUSETTS GENERAL HOSPITAL And … Undereating doesn’t fix obesity … … fixing obesity leads to undereating
- 13. MASSACHUSETTS GENERAL HOSPITAL Physiological vs. counter-physiological weight loss Fat Mass Increased appetitive drive Decreased thermogenesis Pre-treatment Short-term Weight Loss Defended Fat Mass Counter-physiological Weight Loss (e.g., caloric restriction) “Maintenance” Phase Physiological compensation Isolated calorie restriction
- 14. MASSACHUSETTS GENERAL HOSPITAL Physiological vs. counter-physiological weight loss Physiological Weight Loss (e.g., targeted lifestyle change, effective medications, surgery) Fat Mass Pre-treatment Initial Weight Loss Defended Fat Mass Long-term Weight Loss (not a separate phase) Decreased appetitive drive Increased thermogenesis Treatment Initiation
- 15. MASSACHUSETTS GENERAL HOSPITAL GI regulation of metabolic function Energy Balance Metabolic Function Nutrients GI Tract Gut hormones Efferent neurons Immune Cells Appetite, Food Reward Energy Expenditure Metabolic Function Central Mechanisms Liver Pancreas
- 16. MASSACHUSETTS GENERAL HOSPITAL Bariatric and metabolic surgery Vertical Sleeve Gastrectomy Roux-en-Y Gastric Bypass Gastric Adjustable Gastric Banding Biliopancreatic Diversion / Duodenal Switch Gastric and Intestinal Weight-independent Metabolic Benefits MASSACHUSETTS GENERAL HOSPITAL
- 17. MASSACHUSETTS GENERAL HOSPITAL Long-term weight loss after bariatric surgery Carlsson LMS et al. N Engl J Med 2020;383:1535-1543 Swedish Obesity Subjects Study N=2010 surgical patients; 2037 matched controls Operations Gastric bypass 13% Banded gastroplasty 69% Gastric banding 18% Average Weight Loss 1 year post-op 25% 20 years post-op 18%
- 18. MASSACHUSETTS GENERAL HOSPITAL Protective effect of metabolic surgery on COVID-19 outcomes 45% 13% 5.2% 2.4% 2.4% 18% 0% 0% 0% 0% 0% 10% 20% 30% 40% 50% Hospital Admission ICU Admission Mechanical Ventilation Dialysis Death Matched Controls (BMI ≥ 35 kg/m2) Prior Metabolic Surgery Aminian A et al., Surg Obes Rel Dis 2020; epub 25 November 2020
- 19. MASSACHUSETTS GENERAL HOSPITAL Metabolic surgery reduces mortality and extends life Carlsson LMS et al. N Engl J Med 2020;383:1535-1543 Swedish Obesity Subjects Study Mortality reduction 23% Survival increase 3.0 yrs
- 20. MASSACHUSETTS GENERAL HOSPITAL Why is bariatric surgery so effective?
- 21. MASSACHUSETTS GENERAL HOSPITAL 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
- 22. MASSACHUSETTS GENERAL HOSPITAL Bariatric and metabolic surgery 1. Dramatic effects on hunger and satiety 2. Few patients become underweight after surgery 3. Little or no weight loss in thin patients or animals 4. Transient weight gain during pregnancy Clinical Evidence for Physiological Mechanisms
- 23. MASSACHUSETTS GENERAL HOSPITAL The effects of bariatric surgery are fundamentally different from the effects of calorie restriction
- 24. MASSACHUSETTS GENERAL HOSPITAL Gut hormone changes persistently oppose diet-induced weight loss Sumithran et al. NEJM 2011; 365:1597-1604 PYY CCK Amylin Ghrelin
- 25. MASSACHUSETTS GENERAL HOSPITAL GI endocrine responses to RYGB and VSG Time after start of meal (min) 0 20 40 60 80 100 Active GLP-1 (pg/ml) 0 50 100 150 200 250 300 RYGB Sham Lean 5 min mixed meal -10 * # * * * GLP-1 Time after start of meal (min) 0 20 40 60 80 100 PYY (pg/ml) 0 50 100 150 200 250 300 RYGB Sham Lean 5 min mixed meal -10 * * * * * * * Time after start of meal (min) 0 20 40 60 80 100 PYY (pg/ml) 0 50 100 150 200 250 300 RYGB Sham Lean 5 min mixed meal -10 * * * * * * * PYY Time after start of meal (min) 0 20 40 60 80 100 Active Amylin (pg/ml) 0 50 100 150 200 250 5 min mixed meal -10 * * Amylin Time after start of meal (min) 0 20 40 60 80 100 Acylated Ghrelin (pg/ml) 0 50 100 150 200 250 300 RYGB Sham Lean 5 min mixed meal -10 * * Ghrelin Shin et al., 2010
- 26. MASSACHUSETTS GENERAL HOSPITAL Diet RYGB Energy expenditure Appetite Hunger Satiety Reward-based eating Stress response Gut peptides Ghrelin GLP-1, PYY, CCK, amylin RYGB causes changes opposite to those of restrictive dieting Diet RYGB Energy expenditure Appetite Hunger Satiety Reward-based eating Stress response Gut peptides Ghrelin GLP-1, PYY, CCK, amylin
- 27. MASSACHUSETTS GENERAL HOSPITAL How does surgery do this?
- 28. MASSACHUSETTS GENERAL HOSPITAL Vertical sleeve gastrectomy (VSG) induces weight loss Stefater MA et al. Gastroenterology, 2010
- 29. MASSACHUSETTS GENERAL HOSPITAL VSG produces a transient reduction in food intake Stefater MA et al. Gastroenterology, 2010
- 30. MASSACHUSETTS GENERAL HOSPITAL Bariatric surgery leads to defense of a new, lower body fat mass Stefater MA et al. Gastroenterology, 2010
- 31. MASSACHUSETTS GENERAL HOSPITAL Hyperphagia after food restriction is maintained after VSG Stefater MA et al. Gastroenterology 2010
- 32. MASSACHUSETTS GENERAL HOSPITAL Pregnancy increases food intake after VSG Grayson et al., 2012
- 33. MASSACHUSETTS GENERAL HOSPITAL Bariatric/metabolic surgery alters the defended fat mass Defended Fat Mass Normal Obesity After metabolic surgery Decreased appetitive drive Increased thermogenesis Increased appetitive drive Decreased thermogenesis
- 34. MASSACHUSETTS GENERAL HOSPITAL If surgery worked mechanically (restriction or malabsorption) … 0% 10% 20% 30% 40% Surgery Medications Combination … combination with medications would be additive at most Since surgery works physiologically … … complementary mechanisms allow for synergy 0% 10% 20% 30% 40% Surgery Medications Combination
- 35. MASSACHUSETTS GENERAL HOSPITAL Postoperative pharmacotherapy augments surgical weight loss GRAVITAS Study Liraglutide after Gastric Bypass in T2D 0 6 10 18 26 Time (weeks) p<0·0001 p< 0·0001 Change in weight from baseline (kg) 2 0 - 2 - 4 - 6 - 8 Miras AD et al., Lancet Diabetes Endocrinol 2019; 549-559 Placebo Liraglutide 50 40 30 20 10 0 Patients with ≥5% weight loss (%) 0 6 10 18 26 Time (weeks)
- 36. MASSACHUSETTS GENERAL HOSPITAL By what mechanisms does surgery change the body’s defended fat mass?
- 37. MASSACHUSETTS GENERAL HOSPITAL Bariatric surgery illuminates GI regulation of metabolic function CNS and Systemic Effects Luminal Changes (Proximal, Middle and Distal Gut) Roux-en-Y Gastric Bypass Mucosal Interaction Neuronal Immune Hormonal
- 38. MASSACHUSETTS GENERAL HOSPITAL Nutrients • Lipids • Carbohydrates • Proteins / amino acids Pancreatic enzymes Bile acids Microbiota and metabolic products What are the luminal contributors? Luminal Changes (Proximal, Middle and Distal Gut) Roux-en-Y Gastric Bypass Neuronal Immune Hormonal CNS and Systemic Effects
- 39. MASSACHUSETTS GENERAL HOSPITAL Endoluminal regulation of metabolic function NH2 COOH Gastric Bypass Sleeve Gastrectomy Hormonal Neural Immune Bile Acids Nutrients Microbiota Mucosal receptors (for bile acids, nutrients and bacterial products) Mucus • Altered nutrient flow • Accelerated nutrient exposure to small bowel • Altered bile flow • Loss of nutrient interaction with gastric mucosa SCFA Metabolites Signals • Accelerated gastric emptying • Accelerated nutrient exposure to small bowel • Loss of nutrient interaction with gastric mucosa Not foregut… Not hindgut… All of the gut participates
- 40. MASSACHUSETTS GENERAL HOSPITAL Bile acids regulate energy balance Bile Acids Bile Acids BAT Activation L-Cell Activation
- 41. MASSACHUSETTS GENERAL HOSPITAL Patti ME et al., Obesity 2009 Circulating bile acids increase after RYGB RYGB Obesity Over- weight Plasma Bile Acids (μmol/L)
- 42. MASSACHUSETTS GENERAL HOSPITAL RYGB normalizes post-prandial bile acid profile Ahmad NN et al., Intl J Obes 2013
- 43. MASSACHUSETTS GENERAL HOSPITAL Mice colonized with microbiota from a lean donor Mice colonized with microbiota from an obese donor No significant difference in chow consumption, initial body fat, or initial weight Genetic Obesity Dietary Obesity Turnbaugh et al., Nature 2006, Cell Host Microbe 2008 Gut microbiota can transmit adiposity
- 44. MASSACHUSETTS GENERAL HOSPITAL RYGB-specific compositional changes in microbiota Decreased Clostridiales and Erysipelotrichales Increased Enterobacteriales Increased Verrucomicrobiales Liou et al., Sci Transl Med 2013
- 45. MASSACHUSETTS GENERAL HOSPITAL Do these changes contribute to the outcomes after RYGB?
- 46. MASSACHUSETTS GENERAL HOSPITAL RYGB microbiota mediates surgical effects Liou et al., Sci Transl Med 2013 Tremaroli et al., Cell Metab 2015 Obesity Microbiota Germ-Free RYGB Microbiota RYGB Microbiota SHAM Microbiota Germ-Free RYGB SHAM RYGB Microbiota SHAM Microbiota
- 47. MASSACHUSETTS GENERAL HOSPITAL RYGB microbiota not associated with decreased food intake Liou et al., Sci Transl Med 2013
- 48. MASSACHUSETTS GENERAL HOSPITAL RYGB microbiota increases circulating bile acids Mouse Recipients of Human RYGB Microbiota Human RYGB Patients Tremaroli et al., Cell Metab 2015; Ahmad et al., Intl J Obes 2013
- 49. MASSACHUSETTS GENERAL HOSPITAL Identified mechanisms of RYGB • Decreased appetitive drive • Altered food preference • Increased brown/beige thermogenesis • Signaling through MC4R and LepR • Increased circulating bile acids • Altered luminal bile acid pool • Altered microbiota • Altered circadian rhythm regulation • Weight independent improvement in DM • Intestinal epithelial hypertrophy • Altered fat mass set point • Vastly altered global metabolic physiology
- 50. MASSACHUSETTS GENERAL HOSPITAL Mechanisms of action of metabolic surgery
- 51. MASSACHUSETTS GENERAL HOSPITAL How does surgery improve glucose homeostasis?
- 52. MASSACHUSETTS GENERAL HOSPITAL Surgery induces system-wide physiological changes LDL HDL Cholesterol Hunger Energy expenditure Energy Balance Bile acids Δ Gut microbiota GI factors Sweet preference Fat preference Taste GLP-1 PYY Hormones Ghrelin Leptin Insulin sensitivity Beta cell function Glucose Homeostasis
- 53. MASSACHUSETTS GENERAL HOSPITAL Bariatric surgery reduces T2DM incidence Carlsson LMS et al. N Engl J Med 2012; 367:695-704 Swedish Obesity Subjects (SOS) Study
- 54. MASSACHUSETTS GENERAL HOSPITAL Long-term weight loss after bariatric surgery Schauer PR et al., NEJM 2017 STAMPEDE Trial (RCT)
- 55. MASSACHUSETTS GENERAL HOSPITAL Long-term improved glycated hemoglobin Schauer PR et al., NEJM 2017 STAMPEDE Trial
- 56. MASSACHUSETTS GENERAL HOSPITAL Months Following Randomization Benefits of bariatric surgery are not BMI-dependent Schauer PR et al., NEJM 2017 STAMPEDE Trial
- 57. MASSACHUSETTS GENERAL HOSPITAL Effects of surgery on diabetes • Weight loss • Decreased nutrient intake – occurs most dramatically during the first postoperative weeks • Changes in GI physiology or signaling independent of weight loss and food intake – “third mechanism” Potential Mechanisms
- 58. MASSACHUSETTS GENERAL HOSPITAL Acute Effects of RYGB Mimicked by Dietary Restriction Insulin Sensitivity Insulin Secretion Insulin Sensitivity
- 59. MASSACHUSETTS GENERAL HOSPITAL Appetitive differences by feeding site after RYGB Gero et al., Diab Care 2018; 41:1295-1298 Oral Gastric Duodenal Hunger Fullness
- 60. MASSACHUSETTS GENERAL HOSPITAL Glucose regulatory differences by feeding site after RYGB Insulin Glucose Oral Gastric Duodenal Gero et al., Diab Care 2018; 41:1295-1298
- 61. MASSACHUSETTS GENERAL HOSPITAL Incretin secretory differences by feeding site after RYGB Oral Gastric Duodenal GLP-1 GIP Gero et al., Diab Care 2018; 41:1295-1298
- 62. MASSACHUSETTS GENERAL HOSPITAL RYGB has weight and diet-independent effects – 0 20 40 60 80 100 120 0 100 200 300 400 500 Sham RYGB WMSO ** ** ** ** * * * * * * Time (minutes) Glucose (mg/dl) Carmody, Munoz et al., Am J Physiol 2016 long-term Sham-operated (obese) RYGB Underfed, sham-operated to match weight of RYGB mice
- 63. MASSACHUSETTS GENERAL HOSPITAL Control of Diabetes Gastric Banding Gastric Bypass Mechanisms of diabetes improvement Gradual effects Weight Loss Immediate Control of Diabetes X Late (and lasting) effect
- 64. MASSACHUSETTS GENERAL HOSPITAL Interactions of GI Metabolic Regulatory Systems Thermogenesis Microbiota Bile Acids Islet Cell Function Mucosal Hypertrophy Nutrients / Metabolites Nutrients / Metabolites Circadian Rhythms Luminal Extra-Luminal Appetitive Drives
- 65. MASSACHUSETTS GENERAL HOSPITAL The powerful physiological effects of bariatric surgery highlight the critical role of the GI tract in regulating diverse metabolic functions (including energy balance). The many cellular and molecular mechanisms of these GI-based regulatory processes are only now beginning to be understood. A complex system > 25 known appetite-regulating peptides x 6 short-chain fatty acids x 100 bile acids x > 600 bile acid binding proteins x 6 sites of bile acid action x 6 mucins x 5000 nutrients and metabolites x 8000 bacterial strains x Unknown number of unique substrains and genes = Astounding complexity (> 130 quadrillion possibilities) (we are nowhere near replacing bariatric surgery!)
- 66. MASSACHUSETTS GENERAL HOSPITAL No one mechanism appears to dominate the others … For example, evidence to date suggests that changes in the microbiota account for no more than 20% of the weight loss effect of surgery
- 67. MASSACHUSETTS GENERAL HOSPITAL Conclusions 1 – neither restriction nor malabsorption • The true metabolic effectiveness of bariatric surgery appears to reside in its physiological effects • Mechanical effects (e.g., restriction or malabsorption) are much less important • In the absence of profound weight loss (>15-20%), weight loss-independent metabolic effects are particularly important
- 68. MASSACHUSETTS GENERAL HOSPITAL Conclusions 2 – the gut rules • Bariatric surgery has demonstrated a critical role of the gut in regulating metabolic function and energy • This observation has revealed new therapeutic opportunities for treating obesity, type 2 diabetes and other obesity complications, using either surgery itself or “surgicomimetic” therapy • It has also reinforced the importance of GI targets for effective pharmacological treatment of obesity and diabetes • GLP-1 agonists • Amylin agonists • DPP-4 inhibitors
- 69. MASSACHUSETTS GENERAL HOSPITAL Conclusions 3 – evolving mechanistic understanding • Our understanding of how bariatric surgery works – and thus the role of the GI tract in metabolic regulation – has evolved: • Mechanical • Physiological – overdriving the causative pathophysiology • Integration with critical physiological “chokepoints” – dependent on functional regulatory system (e.g., MC4R, LepR, circadian oscillator) • Global influence on GI-metabolic physiology – widespread, broad-based effects that influence multiple known mechanisms, leading to a change in metabolic set points • Little evidence for isolated, parallel mechanisms • Each observed mechanism appears integrated with many others • Few or no “high value” therapeutic targets yet identified
- 70. MASSACHUSETTS GENERAL HOSPITAL Conclusions 4 – bariatric is metabolic • Obesity is a metabolic disease (always) • Whether driven by behavior, environment, genetics, or your mother… … the final common pathway of obesity (excess fat) is physiological (i.e., metabolic) • Effective bariatric surgery is therefore metabolic surgery … … even when used for obesity alone … it causes weight loss by the same mechanisms by which it improves diabetes or fatty liver disease
- 71. MASSACHUSETTS GENERAL HOSPITAL Conclusions 5 – looking forward • The initial goal of identifying both causes and effective treatments of obesity and metabolic disorders through understanding of metabolic surgery remains intact … … but the pharmacological replacement for surgery is less straightforward than initially imagined • Nonetheless, understanding the mechanisms of surgery will reveal important clues about GI regulation of metabolic biology, helping to understand the coordination among different components of these essential homeostatic control systems
- 72. MASSACHUSETTS GENERAL HOSPITAL The powerful physiological effects of bariatric surgery highlight the critical role of the GI tract in regulating diverse metabolic functions (including energy balance). The many cellular and molecular mechanisms of these GI-based regulatory processes are only now beginning to be understood. Take-home message
- 73. MASSACHUSETTS GENERAL HOSPITAL MASSACHUSETTS GENERAL HOSPITAL Why is Bariatric Surgery So Effective? Lee M. Kaplan, MD, PhD Obesity, Metabolism and Nutrition Institute Massachusetts General Hospital LMKaplan@mgh.harvard.edu December 2, 2020 Fernando Botero, 1932-
- 74. Obesity Series 2020 Lee Kaplan, MD, PhD, FTOS Director Obesity, Metabolism, and Nutrition Institute Massachusetts General Hospital Thank you for participating! CLICK HERE to learn more and watch the webinar