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

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

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

5. Energy Intake (EI) = Energy Expenditure (EE) ± Body Energy Stores (S) S ≈ body weight (W) Energy Balance Equation in Response to Overfeeding or Caloric Restriction 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/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 http://pages.csam.montclair.edu/~thomasd/BodePlot.html (Thomas/Heymsfield)

7. Not to Do with 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 VO 2 (EE) by body weight Such a division introduce a mathematical artifact Body Size (Wt, FFM, BSA…) VO 2 (EE)

8. Range > 60,000 kcal Energy Stores Fat 125,000 kcal Protein 40,000 kcal Carbohydrate 2,000 kcal Oxidation as % stores 0.8 1.3 50 Intake as Total Kcal 1,000 500 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. Flatt JP, IJO July 1996 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

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

11. Variability in Respiratory Quotient and Impact on Weight Gain Zurlo F, AJP 259:E650-E657, 1990 Cumulative Incidence of a 5 kg Body Weight Gain (%) Energy Bal % Body Fat Sex Within Subject Method Percentage of Explained Variance 40 20 0 Duration of Follow-up (years) 00.511.522.53 0 20 40 60 80 high RQ > 0.87 Low RQ < 0.82 Family

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

13. Extreme weight loss typically observed only after bariatric surgery 39.6% Ciangura et al. Obesity 2010 3612 -20 kg -30 kg -37 kg 60% 40% 32% 30% 68% 70% Months following gastric bypass 60% loss of excess body weight Buchwald et al. Am J Med. 2009 Loss of substantial lean mass considered detrimental

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 Johannsen et al, in review, 2011

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

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

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

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

21. Correlation between change in leptin and RMR residual in BL (7 mo) and GB (12 mo) participants Johannsen et 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. Energy Balance vs. Substrate Balance Metabolic Adaptation Bariatric Surgery: Energy Metabolism in Animal Studies Bariatric Surgery: Energy Metabolism in Human Studies Weight Loss Physiology: Emphasis on Metabolic Adaptation

24. RYGB induces substantial increase in EE in rats RYGB rats have: 1)Decreased body weight 2)Increased total and resting oxygen consumption 3)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. Zheng, Am J Physiol Regul Integr Comp Physiol, 2009 RYGB rats have higher RER

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 Baseline Month 6 -396 ± 157 kcal/d p<0.001 -3.3 ± 3.6 kcal/kg FFM p<0.05 Fat-free mass (kg) RMR (kcal/day) Values of RMR relative to FFM at baseline (regression line) and month 6 post-surgery 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)

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

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?