Energy Adaptations Persist 2 Years After Sleeve Gastrectomy and Gastric Bypass

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1 OBES SURG (2016) 26: DOI /s BRIEF COMMUNICATION Energy Adaptations Persist 2 Years After Sleeve Gastrectomy and Gastric Bypass Charmaine S. Tam 1 & Georgia Rigas 2 & Leonie K. Heilbronn 3 & Tania Matisan 2 & Yasmine Probst 4 & Michael Talbot 2 Published online: 4 December 2015 # Springer Science+Business Media New York 2015 Abstract Non-surgical weight loss induces a greater than expected decrease in energy expenditure, a phenomenon known as metabolic adaptation. The effects of different bariatric surgery procedures on metabolic adaptation are not yet known and may partially contribute to weight loss success. We compared resting energy expenditure (REE) in 35 subjects (nine males; age=46±11 years; BMI=42.1±6.5 kg/m 2 ) undergoing gastric band, sleeve gastrectomy or Roux-en-Y gastric bypass (RYGB) up to 2 years after surgery. We found a greater than expected reduction of kcal/day at 6 weeks after sleeve and bypass surgery which was not explained by changes in body composition; this change was not seen in the band * Michael Talbot michaelt@upperisugery.com.au Charmaine S. Tam charmaine.tam@sydney.edu.au Georgia Rigas georgiarigas@hotmail.com Leonie K. Heilbronn leonie.heilbronn@adelaide.edu.au Tania Matisan taniam@uppergisurgery.com.au Yasmine Probst yasmine@uow.edu.au The Charles Perkins Centre and School of Biological Sciences, University of Sydney, Sydney, Australia Upper Gastrointestinal Unit, Department of Surgery, St George Private Hospital, Suite 3, Level 5, 1 South St, Kogarah, Australia Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia Smart Foods Centre, School of Medicine, University of Wollongong, Wollongong, NSW, Australia group. The suppression in REE after sleeve and RYGB remained up to 2 years, even after weight loss had plateaued. Our findings suggest that energy adaptation is not a contributing mechanism to medium-term weight maintenance after sleeve and RYGB bariatric surgeries. Keywords Energy expenditure. Resting metabolic rate. Metabolic adaptation Introduction The prevalence of grades 2 and 3 obesity (BMI>35 kg/m 2 ) remains high and increases the risk of developing cardiovascular disease, diabetes and certain cancers. Bariatric surgery is an increasingly popular treatment for morbid obesity because it results in durable and substantial weight loss and improved health and disease outcomes. Similar to non-surgical weight loss methods, bariatric surgery patients often experience a disproportionate loss of fat-free mass. As fat-free mass (FFM) comprises the metabolically active tissues of the body [1], a hypometabolic state (termed metabolic adaptation) may predispose individuals to weight regain, as has been demonstrated after non-surgical weight loss [2]. Given the unique long-term weight maintenance which occurs after bariatric surgery, examining energy metabolism in these patients may shed insight into whether a relative hypermetabolism is a mechanism contributing to sustained weight loss. Knuth et al. found 200 kcal/day deficit in obese patients 6 months after Roux-en-Y gastric bypass (RYGB), although this disappeared by 12 months [3]. It is not known whether metabolic adaptation varies with different bariatric surgery types and whether this response is sustained over time. In the current study, we compared resting energy expenditure (REE) in subjects undergoing gastric band, sleeve

2 460 OBES SURG (2016) 26: gastrectomy or RYGB from 6 weeks and up to 2 years after surgery. We hypothesised that despite losses in metabolically active fat-free mass, bariatric surgery would preserve or increase energy expenditure levels and may be another mechanism contributing to the long-term efficacy of bariatric surgery. and 24 months). The least significant difference method was used for post hoc comparisons. The average degree of energy imbalance was calculated from the measured rates of change of fat mass and fat-free mass along with their respective energy densities of 9.4 and 1.2 kcal/g as previously described [3]. Data are reported as estimated means±standard error. Methods Participants and Study Visits Patients who attended a private bariatric surgery clinic in Sydney, Australia, between October 2010 and November 2014 were invited to participate in the study. Inclusion criteria were abmi>35kg/m 2, age between 18 and 65 years, ability to give informed consent, an absence of previous bariatric or gastric surgery and agreement to use effective contraception and avoid getting pregnant during the trial. As well as usual preand post-operative care, participants underwent metabolic studies 2 months pre-operatively, on the day of the bariatric surgery, and at 6 weeks and 3, 6, 12 and 24 months after surgery. On the day of surgery, patients had been on a 2- week commercially available very low energy diet (VLCD) and post-operatively were on a medically and dieticiansupervised hypocaloric diet typical for post-surgery patients. At each visit, weight and height were measured using a digital scale and calibrated stadiometer after an overnight fast. Resting metabolic rate was measured using a hand-held indirect calorimeter (Medgem, Microlife), and body composition was measured by Bioimpedance (Impedimed, HydexDF50). At baseline, participants had energy intake assessed using 3-day food diaries. Analysis was performed using Foodworks software (version 7, 2012 Xyris Pty Ltd, Springhill, Queensland, Australia) using the AUSNUT2007 database; and glucose, insulin and HbA1c were measured by a commercial pathology laboratory using standard assays. This study was approved by the Human Research Ethics Committee at University of New South Wales, and all participants provided informed consent. Calculation of Metabolic Adaptation and Statistics Analyses were performed using SPSS v.22 and GraphPad Prism 6. Metabolic adaptation was calculated as the difference between measured REE and the REE predicted from fat-free mass, age and sex on the basis of equations established at baseline as previously described [4]. Paired t test was used to examine within-subject changes in each surgery group. At baseline, REE was associated with fat-free mass (P=0.003; Pearson correlation=0.53) and age (P=0.06; Pearson correlation= 0.33). Linear mixed models with a heterogeneous (AR1) repeated covariance type was used to test the effects of group (band, sleeve or bypass) and time (6 weeks, 3, 6, 12 Results Study Participants Forty-nine participants enrolled into the study, of which 14 were excluded (n=7 did not go on to have surgery; n=3 fell pregnant; n=1 received a replacement band; n=3 withdrew from the study). Thirty-five obese patients (nine males; age= 45.8±11.1 years; BMI=42.1±6.5 kg/m 2 ) underwent gastric band (n=8), sleeve gastrectomy (n=13) or RYGB (n=14). Subject characteristics by surgery group are presented in Table 1. Two out of 35 participants were reported to be taking beta-blockers. There were no differences in measured REE between the whole cohort and when these subjects were excluded (data not shown) and therefore, these participants have been included in these analyses. At baseline, the surgery groups were not different in BMI, %fat or glucose, insulin or HbA1c levels although the sleeve group was younger than the RYGB (P=0.05) and band (P=0.006) groups. Energy intake (total energy, absolute amount of carbohydrate, fat or protein) at baseline was not significantly different between groups. Participants attended clinic visits at 6 weeks (8 band; 12 sleeve; 10 RYGB), 3 (8 band; 13 sleeve; 12 RYGB), 6 (8 band; 13 sleeve; 11 RYGB), 12 (8 band; 11 sleeve; 11 RYGB) and 24 months (7 band; 8 sleeve; 8 RYGB). Follow-up rates were 80, 88, 60, 77 and 57 % of the cohort at 6 weeks, 3, 6, 12 and 24 months. Body Weight and Composition The sleeve and RYGB groups demonstrated similar trajectories of weight loss over the 24-month study (Fig. 1). The band group demonstrated steady weight loss followed by a plateau around 6 months, whereas sleeve and RYGB groups did not plateau until 12 months. Twenty-four months after surgery, the band, sleeve and RYGB groups had achieved 16.1±3.2, 30.7 ±2.6 and 32.9±2.7 % total weight loss (%TWL) respectively. For %TWL, there were significant time (P<0.001)and time group interaction effects (P<0.001). At 24 months, the percentage of weight lost as FFM was similar between surgery groups (band 30.5±8.3, sleeve 34.3±7.2, bypass 30.8±2.8). For calculated energy imbalance, there was a significant time effect (P<0.001) but no effect of group or time group (Fig. 1).

3 OBES SURG (2016) 26: Table 1 Participant characteristics at baseline Band Sleeve Bypass N 8 (1 male) 14 (3 males) 13 (5 males) Age (years) 53±9 39.9± ±7.7 Weight (kg) 116.6± ± ±18.7 BMI (kg/m 2 ) 42.0± ± ±5.1 Percent body fat 47.4± ± ±6.4 Biochemistry measures Glucose (mmol/l) 5.7± ± ±2.8 Insulin (pmol/l) 20.8± ± ±6.5 HOMA-IR 5.0± ± ±2.5 Percent HbA1c 4.8± ± ±1.7 Energy intake Total energy (kj/day) 21,811±15,750 24,544± ,097±10,271 Carbohydrates (g/day) 502± ± ±324 Protein (g/day) 328± ± ±110 Fat (g/day) 184± ± ±90 Saturated fat (g/day) 76±59 95±33 88±43 Polyunsaturated fat (g/day) 19±17 30±21 24±14 Monounsaturated fat (g/day) 56±46 87±50 71±30 Data presented as mean±sd. HOMA-IR homeostatic assessment of insulin resistance a) b) 0 6wk 3mth 6mth 12mth 24mth 60 % Total Weight Loss * a * a * a % Body Fat wk 3mth 6mth 12mth 24mth c) wk 3mth 6mth 12mth 24mth Energy Imbalance, kcal/day * b Fig. 1 Changes in body composition in patients undergoing band, sleeve and bypass surgery over 24 months. a Changes in % total weight loss. b Changes in %fat mass. c Changes in energy imbalance. Energy imbalance (kcal/day) was calculated as 9400 (kcal/kg) FM change (kg)+1200 (kcal/kg) FFM change (kg)/t (days). Data is presented as estimated marginal means±sem. Circle with dashed line band, Square with dotted line sleeve, triangle with solid line bypass. *P<0.05 for one-way ANOVA across groups at each time point. a Significant difference (P<0.05) between band and sleeve and band and RYGB. b Significant difference (P<0.05) between band and RYGB

4 462 OBES SURG (2016) 26: Resting Energy Expenditure REE declined over time in all groups (time, P<0.001; group, P=0.93; time group, P=0.02; Table 2). To investigate how much of the decrease in REE was accounted for by changes in body composition, baseline REE data was used to generate a prediction equation using baseline measures of fat-free mass, age and sex (REE predict =1466 kcal/day+8.3 (FFM) 5.8 (age) (sex); r 2 =0.32). Within each time point, the residual between the measured and predicted REE defined the degree of metabolic adaptation. In the sleeve and bypass groups, metabolic adaptation occurred at 6 weeks following surgery and remained lower at 3, 6, 12 and 24 month time points (all P<0.05; Table 2). At 24 months, predicted REE in the sleeve and bypass group was 1701±46 and 1684±48 kcal/ day, which was 346±59 and 279±62 kcal less than observed (P<0.001, P=0.01). In the band group, metabolic adaptation occurred at 6 weeks (P=0.05) and 3 (P=0.005) and 12 months (P=0.06) but was not statistically different from expected at 24 months (P=0.10). Using mixed models, there was a significant group time interaction (P=0.008) for metabolic adaptation, although there were no significant effects of time or group for metabolic Table 2 Changes in resting energy expenditure (REE) in kcal/day after bariatric surgery Measured REE Predicted REE Residual Band Baseline 1505 (145) Week (114) 1651 (64) 112 (68)* Month (135) 1647 (64) 177 (69)* Month (100) 1628 (61) 148 (85) Month (85) 1623 (61) 123 (70) Month (105) 1622 (61) 185 (71) Sleeve Baseline 1762 (105) Week (87) 1767 (49) 305 (52)** Month (104) 1738 (48) 164 (54)* Month (76) 1708 (46) 318 (63)** Month (67) 1705 (46) 277 (56)** Month (87) 1701 (46) 346 (59)** Bypass Baseline 1886 (109) Week (92) 1779 (51) 133 (54)* Month (107) 1742 (50) 200 (53)* Month (82) 1712 (48) 262 (67)** Month (71) 1688 (48) 340 (55)** Month (92) 1684 (48) 279 (62)* Results are presented as estimated measured means (SE). At each time point, metabolic adaptation was calculated as the difference between measured and predicted RMR based on equation developed at baselines using fat-free mass, age and sex (REE predict =1466 kcal/day+8.3 (FFM) 5.8 (age) (sex)). The differences between observed and predicted values at each time-point and within each group were assessed using onesample t test adaptation. Similar results were seen when %TWL was included as a covariate in the model. At 6 weeks, metabolic adaptation was greatest in the sleeve ( 296±59 kcal/day) compared to the bypass ( 133±50 kcal/day; P=0.02) and band ( 131±59 kcal/day; P=0.04) groups. At 12 months, both sleeve ( 348±53 kcal/day; P=0.06) and bypass ( 278 ±57 kcal/day; P=0.01) groups had greater metabolic adaptation compared to the band group ( 190±64 kcal/day). The degree of metabolic adaptation was associated with %TWL at 6 (r=0.47, P=0.01), 12 (r=0.54, P=0.007) and 24 months (r=0.43, P=0.05). There was a trend towards an association between metabolic adaptation and energy imbalance at 12 months (r=0.41, P=0.06). Conclusions This study examined the changes in resting energy expenditure 2 years after band, sleeve and RYGB bariatric surgeries. We found greater than expected reductions in resting energy metabolism 6 weeks after sleeve and bypass surgery which persisted up to 2 years and was not explained by changes in body composition. Interestingly, the suppression in REE remained even after weight loss had plateaued. Metabolic adaptation was only seen at 6 weeks and 3 months after band surgery, which may have been related to smaller energy imbalances in this group. Controversy surrounds the persistence of energy adaptations after surgery-induced weight loss, and few studies have accounted for losses in fat-free mass which is known to affect energy metabolism [3, 5 7]. Carrasco et al. reported a 29 % decrease in TBW 6 months after RYGB, which was accompanied by a 93 kcal deficit in REE [5]. Similarly, total and sleep energy expenditure were decreased 6 months after RYGB in adolescents after adjustment for fat-free mass, fat mass, age and sex [6]. On the other hand, other studies examining REE at 3 and 12 months after RYGB found no differences after adjusting for the effects of fat-free mass and fat mass [8 10]. Our study also found that all three bariatric surgery types resulted in similar losses of fat-free mass (31 34 %) after 24 months [11]. To our knowledge, our results provide the longest follow-up of the changes in energy expenditure whilst accounting for changes in body composition, after different types of bariatric surgery. Potential limitations of our study may be the use of bioelectrical impedance and handheld indirect calorimetry for measuring body composition and REE, although both these techniques have been validated against gold standard techniques. In conclusion, our results suggest that energy adaptation does not directly contribute to medium-term weight loss maintenance associated with sleeve gastrectomy and RYGB. However, investigations examining mediators of this energy adaptation such as sympathetic

5 OBES SURG (2016) 26: nervous system activity, leptin and thyroid hormones are required. Compliance with Ethical Standards All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Conflict of Interest All authors declare no conflict of interest. Informed Consent Informed consent was obtained from all individual participants included in the study. References 1. Muller MJ, Bosy-Westphal A, Kutzner D, et al. Metabolically active components of fat-free mass and resting energy expenditure in humans: recent lessons from imaging technologies. Obes Rev. 2002;3(2): Rosenbaum M, Hirsch J, Gallagher DA, et al. Long-term persistence of adaptive thermogenesis in subjects who have maintained a reduced body weight. Am J Clin Nutr. 2008;88(4): Knuth ND, Johannsen DL, Tamboli RA, et al. Metabolic adaptation following massive weight loss is related to the degree of energy imbalance and changes in circulating leptin. Obesity (Silver Spring). 2014;22(12): Heilbronn LK, de Jonge L, Frisard MI, et al. Effect of 6-month calorie restriction on biomarkers of longevity, metabolic adaptation, and oxidative stress in overweight individuals: a randomized controlled trial. JAMA. 2006;295(13): Carrasco F, Papapietro K, Csendes A, et al. Changes in resting energy expenditure and body composition after weight loss following Roux-en-Y gastric bypass. Obes Surg. 2007;17(5): Butte NF, Brandt ML, Wong WW, et al. Energetic adaptations persist after bariatric surgery in severely obese adolescents. Obesity (Silver Spring). 2015;23(3): Faria SL, Faria OP, Cardeal MA, et al. Diet-induced thermogenesis and respiratory quotient after Roux-en-Y gastric bypass surgery: a prospective study. Surg Obes Relat Dis. 2014;10(1): Das SK, Roberts SB, McCrory MA, et al. Long-term changes in energy expenditure and body composition after massive weight loss induced by gastric bypass surgery. Am J Clin Nutr. 2003;78(1): Dirksen C, Jorgensen NB, Bojsen-Moller KN, et al. Gut hormones, early dumping and resting energy expenditure in patients with good and poor weight loss response after Roux-en-Y gastric bypass. Int J Obes (Lond). 2013;37(11): de Castro CM, de Lima Montebelo MI, Rasera Jr I, et al. Effects of Roux-en-Y gastric bypass on resting energy expenditure in women. Obes Surg. 2008;18(11): Fruhbeck G. Bariatric and metabolic surgery: a shift in eligibility and success criteria. Nat Rev Endocrinol. 2015;11(8):