Weight Loss Physiology: Emphasis on Metabolic Adaptation Eric Ravussin, Ph.D

1. Weight Loss Physiology: Emphasis on Metabolic Adaptation Eric Ravussin, Ph.D Minimally Invasive Surgery Symposium February 21-26, 2011; Salt Lake City, UT

2. BARIA Study Goal: 48 subjects (12/group) n=1 n=4 n=2 n=4 Funded by Ethicon Surgery

3. Weight Loss Physiology: Emphasis on Metabolic Adaptation • Energy Balance vs. Substrate Balance • Metabolic Adaptation • Bariatric Surgery: Energy Metabolism in Animal Studies • Bariatric Surgery: Energy Metabolism in Human Studies

4. Genes Intake Body Weight Expenditure Loss Gain Stable Environment Etiology of Overweight and Obesity The Energy Balance Equation

5. Energy Balance Equation in Response to Overfeeding or Caloric Restriction Energy Intake (EI) = Energy Expenditure (EE) ± Body Energy Stores (S) S ≈ body weight (W) Going from stable energy balance to 500 Kcal/d negative energy balance is not as simple as 1 pound of weight loss a week (¾ FM and ¼ FFM) because: - The energy content of weight change is not constant - The fraction of weight loss as FFM is not constant - Energy expenditure changes in response to weight loss

6. Body Weight Simulators http://www4.niddk.nih.gov/lbm/ (Kevin Hall; NIDDK) Web-based dynamic simulation model of adult human metabolism that predicts the time course of individual body weight change in response to a prescribed behavioral intervention. http://pages.csam.montclair.edu/~thomasd/BodePlot.html(Thomas/Heymsfield)

7. Not to Dowith Data from Energy Balance And Energy Expenditure • Energy Balance • Do not extrapolate an Energy Gap (kcal/d) over time • The rule of 1 pound of weight loss a week for 500kcal/day deficit is wrong • Energy Expenditure • Do not divide VO2 (EE) by body weight • Such a division introduce a mathematical artifact VO2 (EE) Body Size (Wt, FFM, BSA…)

8. Energy Stores Range > 60,000 kcal Intake as Total Kcal Oxidation as % stores Fat 125,000 kcal 1,000 0.8 500 Protein 40,000 kcal 1.3 Carbohydrate 2,000 kcal 50 1,000 Daily Nutrient Balance (70kg Man; 20% Fat) on 2500 kcal/d Diet (40% fat, 40% CHO , 20 % Protein) Range for up to 150-kg Man Fat Intake = Fat Oxidation; Prot Intake = Prot Oxidation CHO Intake = CHO Oxidation; Alcohol Intake = Alcohol Oxidation

9. Regulation of Nutrients Balance: FQ/RQ Concept Fat intake is poorly regulated because of the relatively small daily flux relative to the large pool size Flatt JP, IJO July 1996

10. Fat Balance vs. Energy Balance • Energy balance is buffered by fat balance • Positive energy balance = fat gain • Negative energy balance = fat loss Abbott WGH, et al. AJP 1988;255:E332-7

11. Variability in Respiratory Quotient and Impact on Weight Gain Within Subject Method 80 40 high RQ > 0.87 60 Family Percentage of Explained Variance 5 kg Body Weight Gain (%) Cumulative Incidence of a 40 20 20 Energy Bal Low RQ < 0.82 % Body Fat Sex 0 0 0 0.5 1 1.5 2 2.5 3 Duration of Follow-up (years) Zurlo F, AJP 259:E650-E657, 1990

12. Weight Loss Physiology: Emphasis on Metabolic Adaptation • Energy Balance vs. Substrate Balance • Metabolic Adaptation • Bariatric Surgery: Energy Metabolism in Animal Studies • Bariatric Surgery: Energy Metabolism in Human Studies

13. Extreme weight loss typically observed only after bariatric surgery 39.6% Months following gastric bypass 3 6 12 40% 32% 30% 60% 68% 70% -20 kg -30 kg -37 kg 60% loss of excess body weight Loss of substantial lean mass considered detrimental Ciangura et al. Obesity 2010 Buchwald et al. Am J Med. 2009

14. Does exercise attenuate fat-free mass loss and decrease metabolic adaptation during weight loss? • Very-low calorie diets (including surgically-induced) result in rapid weight loss with substantial loss of FFM • Limited data suggests that exercise may preserve lean tissue during significant weight loss Question What are the effects of large weight losses (mediated through extreme exercise plus calorie restriction) on body composition and metabolic adaptation?

16. Participant Characteristics Age: 36 years (20-56 y old) 4 males, 7 females Johannsenet al, in review, 2011

17. Intensive “Lifestyle Intervention” Resulted in Conservation of Lean Mass Week 6 Week 30 Week 6 Week 30 19% 80% -19 ± 3 % -15 ± 5 kg 81% -73 ± 16 % -58 ± 25 kg Johannsenet al, in review, 2011

18. Metabolic Adaptation Occurs despiteLeanMass Preservation Predicted RMR = 1,241 + 19.2 FFM + 1.8 FM – 9.8 age + 405 (male) Baseline Week 6 Week 30 -244 ± 231 -504 ± 171 p=0.006 p<0.001 Johannsenet al, in review, 2011

19. The Metabolic Adaptation Occurred Early in the Intervention Johannsenet al, in review, 2011

20. Determinants of the Metabolic Adaptation CR ↓ leptin ↓ SNS ↓ Gonadal axis ↓ Thyroid hormones ↓ Energymetabolism = metabolic adaptation

21. Correlation between change in leptin and RMR residual in BL (7 mo) and GB (12 mo) participants Johannsenet al, in review, 2011

22. Summary and Question • An intensive lifestyle intervention (vigorous daily exercise and self-selected calorie restriction) results in extreme weight loss with preservation of lean mass • Despite the preservation in lean mass, significant metabolic adaptation occurred Does a similar “Metabolic Adaptation” happen after bariatric surgery?

23. Weight Loss Physiology: Emphasis on Metabolic Adaptation • Energy Balance vs. Substrate Balance • Metabolic Adaptation • Bariatric Surgery: Energy Metabolism in Animal Studies • Bariatric Surgery: Energy Metabolism in Human Studies

24. RYGB induces substantial increase in EE in rats • RYGB rats have: • Decreased body weight • Increased total and resting oxygen consumption • Lower RQ Stylopoulos, Obesity, 2009

25. RYGB-stimulated increases in EE are dependent on food ingestion • RYGB rats have: • Higher resting V02 during ad lib refeeding and not during fasting • Higher core body temperature Stylopoulos, Obesity, 2009

26. RYGB rats have higher RER Zheng, Am J PhysiolRegulIntegr Comp Physiol, 2009

27. Energy Balance: Emphasis on Metabolic Adaptation with Bariatric Surgery • Energy Balance vs. Substrate Balance • Metabolic Adaptation • Bariatric Surgery: Energy Metabolism in Animal Studies • Bariatric Surgery: Energy Metabolism in Human Studies

28. Decreased measured and predicted REE after RYGB in 20 obese women Bobbioni-Harsch, JCEM, 2000

29. Increased fat oxidation after RYGB in 20 obese women Bobbioni-Harsch, JCEM, 2000

30. Metabolic adaptation occurs with surgically-induced weight loss Carrasco et al. Obes Surg. 2007 Ratio of REE/FFM was reduced from 33.4 to 30.1 kcal/kg (P<0.05) RQ decreased from 0.86 to 082 (P<0.05) -396 ± 157 kcal/d p<0.001 Values of RMR relative to FFM at baseline (regression line) and month 6 post-surgery -3.3 ± 3.6 kcal/kg FFM p<0.05 RMR (kcal/day) Baseline Month 6 Fat-free mass (kg)

31. TEE and SMR are decreased after vertical banded gastroplasty(8 obese) Van Gemert, IJO, 2000

32. Lipid oxidation is increased after vertical banded gastroplasty in 8 obese subjects Van Gemert, IJO, 2000

33. Conclusions from Human Energy Metabolism Data after Bariatric Surgery (Bypass) • Generally, gastric bypass seems to decrease the magnitude of the metabolic adaptation • Gastric bypass seems to increase lipid oxidation Question? What are the mechanisms underlying the favorable energy metabolism profile after gastric bypass?