Energetic adaptations in response to RYGB‐induced weight loss are associated with changes in insulin, adipokines, thyroid hormones, gut hormones, and sympathetic nervous system activity and persists 12 months postsurgery.

In the RYGB group, mean weight loss was 44 ± 19 kg at 12 months. Total energy expenditure (TEE), activity EE, basal metabolic rate (BMR), sleep EE, and walking EE significantly declined by 1.5 months ( P = 0.001) and remained suppressed at 6 and 12 months. Adjusted for age, sex, fat‐free mass, and fat mass, EE was still lower than baseline ( P = 0.001). Decreases in serum insulin, leptin, and triiodothyronine (T3), gut hormones, and urinary norepinephrine (NE) paralleled the decline in EE. Adjusted changes in TEE, BMR, and/or sleep EE were associated with decreases in insulin, homeostatic model assessment, leptin, thyroid stimulating hormone, total T3, peptide YY3‐36, glucagon‐like peptide‐2, and urinary NE and epinephrine ( P = 0.001‐0.05).

At baseline and at 1.5, 6, and 12 months post‐baseline, 24‐h room calorimetry, body composition, and fasting blood biochemistries were measured in 11 obese adolescents relative to five matched controls.

Energetic adaptations induced by bariatric surgery have not been studied in adolescents or for extended periods postsurgery. Energetic, metabolic, and neuroendocrine responses to Roux‐en‐Y gastric bypass (RYGB) surgery were investigated in extremely obese adolescents.

Introduction Bariatric surgery induces massive reductions in body weight that are associated with energetic adaptations that favor weight regain (1). These adaptations involve multiple signals including regulatory hormones from the gastrointestinal tract and pancreas impacting glucose homeostasis, adipokines affecting inflammation and insulin resistance, and the hypothalamic–pituitary axis regulating energy balance in part through thyroid, autonomic nervous system, and adrenal mediators (2, 3). The metabolic changes induced by bariatric surgery result in resolution or improvement in obesity‐related comorbidities including type 2 diabetes, hyperlipidemia, liver disease, obstructive sleep apnea, pseudotumor cerebri, hypertension, and psychological disorders (3). Inevitably, bariatric surgery induces some loss of fat‐free mass (FFM), which is undesirable as FFM is responsible for the majority of basal metabolism, regulation of core body temperature, cardiopulmonary function, and skeletal integrity and mobility. For extremely obese adolescents who have been unable to achieve a healthy weight with conventional treatment, Roux‐en‐Y gastric bypass (RYGB) surgery is an option (4). RYGB is a diversionary procedure which creates a very small gastric pouch considerably restricting meal size and promoting early satiety. A surgical anastomosis connects the gastric pouch to the mid‐jejunum using a 125‐150 cm Roux limb, diverting ingested macronutrients and micronutrients from the duodenum, decreasing the efficiency of micronutrient absorption (5). Dietary energy restriction and weight loss elicit energetic adaptations or compensatory changes in energy expenditure (EE) that are greater than that accounted for by the residual active tissue mass (6). Decreased sympathetic nervous system (SNS) tone and circulating concentrations of leptin and thyroid hormones act coordinately to favor weight regain. Energetic adaptations to bariatric surgery have been documented in adults mainly using portable respiration calorimeters (7) and also room respiration calorimetry (8) and doubly labeled water (9). Persistence of energetic adaptations beyond the period of active weight loss by conventional means (6, 10) or bariatric surgery remains controversial (7). Studies demonstrate prolonged reduction in EE (6, 11, 12), whereas others show no persistence (13, 14). Whether energetic adaptations occur and persist in maturing adolescents is critical to understand the mechanisms of weight loss maintenance, and in particular, recidivism after RYGB surgery. The primary study objective was to investigate energetic, metabolic, and neuroendocrine responses to RYGB surgery in extremely obese adolescents at 1.5, 6, and 12 months after surgery. Specific aims were to 1) monitor changes in weight and body composition using a multicompartment model, 2) measure changes in neuroendocrine factors, 3) measure 24‐h EE and substrate utilization using room respiration calorimetry, and 4) identify neuroendocrine factors associated with the changes in EE and substrate utilization.

Methods Human subjects A 12‐month prospective study design was used to investigate energetic, metabolic, and neuroendocrine responses to RYGB surgery (n = 11) in extremely obese adolescents. A control group (n = 5) matched for initial weight, body mass index (BMI), and body composition was used to ascertain effects due to extreme obesity itself or protocol procedures. Anthropometry, body composition, 24‐h room respiration calorimetry, and 12‐h fasting blood and 24‐h urine samples for neuroendocrine biochemistries were measured at baseline and at 1.5, 6, and 12 months post‐baseline to represent the following presurgical (baseline) and postsurgical phases: rapid weight loss (1.5 months after surgery), moderate weight loss (6 months after surgery), and minimal weight loss or weight maintenance (12 months after surgery). Controls were studied at baseline and at 1.5, 6, and 12 months post‐baseline. Subjects were recruited from the Texas Children's Hospital Adolescent Bariatric Surgery Program. Adolescents electing surgery (RYGB group) or declining surgery and not enrolled in conventional weight loss programs (controls) were asked to participate. Inclusion criteria were Tanner stage IV or V and BMI ≥ 50 kg/m2 or BMI ≥ 40 kg/m2 with comorbidities. Exclusion criteria included a positive urine pregnancy test and serious psychiatric or cognitive disorders. Study participation did not interfere with the routine clinical care of the patients undergoing RYGB surgery. Following bariatric surgery, regular and frequent follow‐up visits assessed weight loss and monitored for postoperative complications, dietary progression, and adequacy of physical activity. Immediately postoperative until day 2, the patients ingested only clear liquids. Thereafter, patients were slowly advanced from a sugar‐free full liquid diet to a soft diet and finally to a regular diet. By 6 months postsurgery, the diet prescription was a regular diet consisting of three meals and two snacks per day, with an emphasis on high protein sources. A multivitamin mineral supplement with iron and supplemental calcium were prescribed. Anthropometry Body weight to the nearest 0.1 kg was measured with a digital scale (model TBF‐410; Tanita Corporation, Arlington Heights, IL) and height to the nearest 1 mm was measured with a stadiometer (model 226l; Seca, Chino, CA). Waist circumference was measured using a nonextensible metal tape measure. Body composition Body composition was estimated using the Fuller three‐compartment model based on total body water (TBW) and body volume (15). TBW was measured by the 2H isotope dilution following an oral dose (0.04 g/kg body weight) of deuterium oxide (2H 2 O). 2H abundances of baseline and 4‐ and 6‐h post‐dose urine samples were measured by gas‐isotope‐ratio mass spectrometry (16, 17). Body volume and body density were measured by air‐displacement plethysmography using the BodPod (Life Measurements, Concord, CA). Blood chemistries Serum glucose (Analox Instruments, Lundeburg, MA) and nonesterified fatty acids (NEFAs) were measured by enzymatic colorimetric techniques (Wako Diagnostics, Richmond, VA). Enzyme‐linked immunosorbent assays (ELISA) were used to measure serum insulin, resistin, adiponectin, and glucagon‐like peptide‐2 (GLP2; Millipore, Billerica, MD) and C‐reactive protein (CRP; Alpco Diagnostics, Salem, NH). Homeostatic model assessment (HOMA) was used to quantify insulin resistance (18). Radioimmunoassays were used to measure serum leptin, peptide YY3‐36 (PYY3‐36), and glucagon‐like peptide‐1 (GLP1; EMD Millipore, Billerica, MA) and thyroid stimulating hormone (TSH), total and free thyroxine (T4), and triiodothyronine (T3) and reverse T3 (Siemens, Deerfield, IL). ELISAs were used to quantify urinary norepinephrine (NE) and epinephrine (E; Rocky Mountain Diagnostics, Colorado Springs, CO). Urinary nitrogen concentrations were determined by Kjeldahl digestion (Kjeltec Auto Analyzer 1030; Tecator, Hoganas, Sweden) and a phenol‐hypochlorite colorimetric reaction (19). Room respiration calorimetry protocol Energy expenditure was measured for 24 h in one of the two large (34 m3) calorimeters. The design, instrumentation, and performance of the calorimeters have been published (20). During the 24‐h calorimetry, subjects adhered to a schedule of physical activity (treadmill walking), feeding, and sleeping. Heart rate and physical activity were recorded using Actiheart (CamNtech, Cambridge, UK). From the VO 2 , VCO 2 , and urinary nitrogen excretion, total EE (TEE), nonprotein EE, respiratory quotient (RQ), and net substrate utilization (21) were measured. During 24‐h calorimetry, the diet prescribed for the patients undergoing RYGB was served to both the RYGB group and controls. Food intake was provided as three meals and two snacks with a macronutrient composition consisting of 30% protein, 25% fat, and 45% carbohydrate. Food intake was offered at 1.2 times basal metabolic rate (BMR) predicted for obese adolescents at baseline and at 600, 1,100, and 1,400 kcal/day at 1.5, 6, and 12 months post‐baseline, respectively. BMR was measured after a 12‐h fast on awakening for 30 min. Sleeping EE was measured for the entire night sleep period, as confirmed by heart rate and motion sensors. Activity EE (AEE) was computed as TEE‐BMR‐0.1TEE assuming diet‐induced thermogenesis to be 10% of TEE. Physical activity level (PAL) was defined as TEE/BMR. Energy cost of walking was measured while walking at 2.5 mph for 15 min on a treadmill (Vision Fitness T9600; ref. (22). The energy economy of walking [kcal/(kg km)] was calculated as the ratio of the net EE standardized by weight per minute [kcal/(kg min)] divided by speed (km/min). Statistical methods Statistical analysis was performed using STATA (version 13.0; StataCorp, College Station, TX) and SAS (SAS Institute, Cary, NC). Independent t tests for continuous variables and χ2 tests for categorical variables were used for descriptive analyses. A nonlinear regression with an exponential decay model was used to fit the weight data of the RYGB group (GraphPad Software, La Jolla, CA). A linear mixed‐effects regression model for repeated measures was used where subjects were treated as random effects and group assignment (RYGB group or controls), measurement time from baseline, and potential interactions between group and time as fixed effects. As necessary, natural logarithms were used to transform data to better satisfy the linearity and distributional assumptions. Post hoc comparisons using Tukey‐Kramer for multiple comparisons with two‐tailed statistical tests between time points were performed.

Results A total of 11 adolescents (3M/8F) electing RYGB surgery and five controls (3M/2F) participated in this study. Mean age at enrollment was 16.5 ± 0.8 years in the RYGB surgery and 14.8 ± 1.2 years in controls (P = 0.03). At baseline, weight, height, BMI, waist circumference, body volume, FFM, FM, and percent FM did not differ between RYGB group and controls. Anthropometry and body composition of the RYGB group and controls are summarized in Table 1. Adjusted for age and sex, significant group × time interactions were observed for all parameters (P = 0.000‐0.019). Highly significant (P = 0.001) time effects for weight, BMI, waist circumference, and the body composition parameters were seen for the RYGB group only. Table 1. Anthropometric and body composition of the RYGB group (n = 11) and controls (n = 5) Post‐baseline Time effect within Baseline 1.5 months 6 months 12 months group (P‐value) Post hoc testa Weight (kg) RYGB 153.1 ± 28.7b 136.9 ± 27.5 117.3 ± 30.6 106.6 ± 26.3 <0.0001 ab, ac, ad, bd Control 133.2 ± 24.9 133.0 ± 27.4 134.7 ± 31.6 131.4 ± 30.7 0.929 Height (m) RYGB 1.64 ± 0.07 1.64 ± 0.07 1.64 ± 0.05 1.64 ± 0.07 0.197 NS Control 1.65 ± 0.06 1.66 ± 0.06 1.67 ± 0.06 1.68 ± 0.06 0.800 BMI (kg/m2) RYGB 57.0 ± 10.5 50.9 ± 10.4 45.3 ± 11.2 40.1 ± 10.7 <0.0001 ab, ac, ad, bc, bd Control 48.0 ± 8.7 48.3 ± 9.2 47.9 ± 10.3 46.0 ± 9.1 0.809 Waist circumference (cm) RYGB 133.7 ± 16.2 126.9 ± 21.3 115.9 ± 18.6 110.8 ± 18.0 0.016 ac, ad, bc, bd Control 122.9 ± 16.0 127.2 ± 19.2 119.5 ± 19.4 119.2 ± 21.4 0.229 Body volume (l) RYGB 146.5 ± 24.6 139.3 ± 29.4 117.9 ± 32.6 105.3 ± 28.3 <0.0001 ab, ac, ad, bc, bd Control 131.4 ± 28.7 134.0 ± 29.3 127.0 ± 31.4 131.3 ± 31.1 0.889 TBW (kg) RYGB 54.1 ± 8.7 48.3 ± 7.8 46.2 ± 8.6 47.3 ± 10.3 0.001 ab, ac, ad Control 49.4 ± 6.3 49.3 ± 5.8 50.2 ± 7.31 51.9 ± 8.70 0.441 FFM (kg) RYGB 72.9 ± 10.8 65.3 ± 9.6 62.8 ± 10.1 65.0 ± 12.6 0.001 ab, ac, ad Control 66.0 ± 8.0 67.9 ± 8.1 68.3 ± 8.1 72.1 ± 13.5 0.352 FM (kg) RYGB 80.3 ± 20.9 71.6 ± 21.0 54.6 ± 21.9 41.5 ± 22.2 <0.0001 ab, ac, ad, bc, bd, cd Control 67.1 ± 17.0 65.1 ± 21.1 66.4 ± 23.7 59.3 ± 17.8 0.882 FM (% weight) RYGB 51.8 ± 5.2 51.6 ± 6.0 44.9 ± 8.6 37.0 ± 12.9 0.002 ac, ad, bc, bd Control 49.8 ± 4.1 47.8 ± 7.8 47.8 ± 7.9 44.4 ± 4.7 0.738 In the RYGB group, mean total weight lost was 44 ± 19 kg or 30% ± 11% of initial body weight at 12 months. Mean weight loss was −16, −18, and −10 kg from baseline to 1.5 months, 1.5 to 6 months, and 6 to 12 months, equivalent to 11%, 14%, and 9% of initial body weight, respectively. Substantial variation was seen in the rate of weight loss (299 ± 120 g/day during the first 1.5 months, 110 ± 62 g/day between 1.5 and 6 months, and 48 ± 45 g/day between 6 and 12 months). Based on multiple clinical weights, individual patterns of weight loss in the RYGB group were described by a negative exponential function (mean r2 = 0.98; Figure 1). By 12 months, weight loss had reached a plateau in all (−5 ± 5 g/day) but two RYGB participants (−51 g/day and −77 g/day). No change in height was observed over the period of study in either group. Figure 1 Open in figure viewer PowerPoint Patterns of weight loss in adolescents undergoing RYGB surgery described by a negative exponential function. Body composition changed significantly in the RYGB group (P < 0.001), but not in the controls. TBW and FFM loss occurred primarily in the first 1.5 months after surgery, with only minor (nonsignificant) changes thereafter. Hydration of FFM averaged 73.4% and did not differ by group or time. Total FFM loss averaged 8.3 ± 3.7 kg or 12% ± 5% of initial FFM. In contrast, FM decreased steadily over the 12 months postsurgery; total FM loss was 36 ± 20 kg or 47 ± 22% of initial FM. Fasting blood chemistries and 24‐h urinary catecholamines are presented in Table 2. Adjusted for age and sex, significant group × time interactions were seen for all parameters (P = 0.0012‐0.048). Further analysis revealed significant time effects for the RYGB group only. NEFA increased significantly in the RYGB group 1.5 months after surgery and then declined (P = 0.001). Glucose was significantly lower than baseline at 1.5, 6, and 12 months postsurgery (P = 0.001). Insulin and consequently HOMA were significantly lower after surgery (P = 0.001). Adiponectin steadily increased and leptin decreased postsurgery (P = 0.001), but resistin did not change. The inflammation marker CRP declined postsurgery (P = 0.01). Thyroid status was altered by RYGB surgery: fasting serum TSH (P = 0.03) and total T3 (P = 0.003) decreased postsurgery. Significant changes were not seen in total T4, reverse T3, or free T3 or T4. Fasting levels of PPY3‐36 and GLP2 declined (P = 0.001), but GLP1 did not change. Urinary excretion of NE, but not of E, decreased after surgery (P = 0.01). Table 2. Fasting blood chemistries and 24‐h urinary catecholamines of the RYGB group (n = 11) and controls (n = 5) Post‐baseline Time effect within Baseline 1.5 months 6 months 12 months group (P‐value) Post hoc testa NEFA (mEq/l) RYGB 0.72 ± 0.26b 0.92 ± 0.23 0.61 ± 0.17 0.49 ± 0.17 0.014 ab, bc Control 0.60 ± 0.11 0.70 ± 0.21 0.68 ± 0.17 0.70 ± 0.26 0.704 Glucose (mg/dl) RYGB 102.3 ± 21.4 91.6 ± 7.7 85.9 ± 7.1 86.8 ± 8.5 0.037 ab, ac, ad Control 95.1 ± 6.0 98.2 ± 11.4 99.0 ± 7.3 98.9 ± 7.1 0.547 Insulin (μU/ml) RYGB 34.5 ± 24.0 13.1 ± 8.8 12.7 ± 7.1 9.1 ± 5.4 0.006 ab, ac, ad Control 29.0 ± 10.4 23.1 ± 8.5 21.6 ± 11.6 22.8 ± 13.9 0.472 HOMA RYGB 8.1 ± 4.8 2.9 ± 1.7 2.6 ± 1.3 1.9 ± 1.1 0.001 ab, ac, ad Control 6.7 ± 2.1 5.5 ± 1.7 5.2 ± 2.7 5.5 ± 3.3 0.600 Adiponectin (ng/ml) RYGB 6,474 ± 2,540 8,422 ± 2,688 8,634 ± 3,620 10,900 ± 4,820 0.002 ab, ac, ad, bd, cd Control 6,873 ± 4,331 6,686 ± 4,229 7,088 ± 4,936 7,690 ± 6,502 0.909 Resistin (ng/ml) RYGB 11.79 ± 2.82 12.11 ± 4.46 12.47 ± 3.03 12.55 ± 3.88 0.931 NS Control 9.44 ± 3.30 10.49 ± 2.76 10.90 ± 6.16 7.96 ± 2.45 0.714 Leptin (ng/ml) RYGB 71.0 ± 36.6 42.7 ± 24.5 35.8 ± 21.9 25.4 ± 24.1 0.001 ab, ac, ad Control 66.2 ± 22.5 52.8 ± 19.1 60.0 ± 25.0 43.0 ± 14.9 0.238 CRP (ng/ml) RYGB 11,360 ± 9,801 4,546 ± 3,455 6,945 ± 5,986 3,160 ± 4,795 0.016 Control 6,433 ± 5,537 6,172 ± 3,487 7,252 ± 3,557 5,500 ± 4,400 0.666 TSH (μIU/ml) RYGB 3.05 ± 1.36 2.10 ± 0.80 1.47 ± 0.51 1.65 ± 0.94 0.031 ab, ac, ad Control 1.77 ± 0.97 1.66 ± 0.69 1.77 ± 1.01 1.58 ± 1.21 0.768 Total T3 (ng/dl) RYGB 115.0 ± 30.7 82.3 ± 23.8 91.5 ± 26.8 77.7 ± 17.9 0.003 ab, ad Control 111.9 ± 37.2 104.1 ± 32.4 104.7 ± 32.6 97.1 ± 13.5 0.233 Total T4 (μg/dl) RYGB 7.77 ± 1.65 7.14 ± 1.64 7.82 ± 3.18 7.32 ± 1.23 0.480 NS Control 6.18 ± 1.49 6.39 ± 0.97 6.20 ± 1.29 6.10 ± 2.47 0.027 Free T3 (pg/ml) RYGB 3.34 ± 0.49 2.82 ± 0.60 2.72 ± 0.57 2.59 ± 0.51 0.203 Control 3.52 ± 0.70 3.27 ± 1.10 3.08 ± 0.93 3.14 ± 0.44 0.554 Free T4 (ng/dl) RYGB 1.31 ± 0.18 1.19 ± 0.22 1.29 ± 0.30 1.26 ± 0.25 0.525 NS Control 1.10 ± 0.18 1.22 ± 0.16 1.15 ± 0.18 1.18 ± 0.43 0.541 Reverse T3 (ng/ml) RYGB 0.33 ± 0.08 0.34 ± 0.09 0.32 ± 0.08 0.27 ± 0.04 0.120 bd Control 0.24 ± 0.08 0.27 ± 0.05 0.22 ± 0.06 0.20 ± 0.08 0.026 PYY3‐36 (pg/ml) RYGB 105.2 ± 24.6 68.1 ± 20.8 89.5 ± 14.5 77.8 ± 28.4 0.001 ab, ad, bc Control 77.0 ± 23.5 58.4 ± 22.4 72.1 ± 32.6 84.2 ± 17.0 0.240 GLP1 (pM) RYGB 16.1 ± 6.0 17.2 ± 10.3 15.6 ± 8.1 13.0 ± 6.6 0.903 Control 13.1 ± 3.7 13.5 ± 7.2 8.6 ± 4.8 15.8 ± 10.1 0.365 GLP2 (ng/ml) RYGB 8.63 ± 1.83 5.38 ± 2.07 5.97 ± 0.65 6.23 ± 1.87 0.001 ab, ac Control 5.58 ± 2.35 5.33 ± 2.03 6.64 ± 1.45 6.25 ± 2.55 0.341 Urinary NE (nmol/day) RYGB 326 ± 166 232 ± 168 250 ± 92 205 ± 91 0.014 Control 296 ± 62 218 ± 86 300 ± 175 311 ± 105 0.632 Urinary E (nmol/day) RYGB 49.1 ± 14.8 42.5 ± 41.5 53.0 ± 19.1 43.3 ± 14.1 0.604 Control 47.3 ± 9.1 48.2 ± 17.2 45.7 ± 32.1 57.8 ± 29.1 0.643 Total EE and its components measured by 24‐h calorimetry are summarized in Table 3. Adjusted for age and sex, significant group × time interactions were seen for TEE and its components (P = 0.001‐0.01); significant time effects were observed in the RYGB group, but not controls. TEE, BMR, and sleep EE declined by 24%, 19%, and 24% at 1.5 months, and then remained at the suppressed level at 6 and 12 months after surgery. Adjusted for age, sex, FFM, and FM, postsurgical TEE (kcal/day), BMR (kcal/min), and sleep EE (kcal/min) were still significantly lower than baseline (P = 0.001). TEE, BMR, and sleep EE as a function of FFM are graphically displayed in Figure 2; the downward shift in TEE, BMR, and sleep EE occurred in the initial 1.5 months postsurgery and then persisted. Similar to the pattern in EE, heart rate throughout the 24‐h decreased significantly at 1.5 months after surgery (P = 0.001) and remained at the lower level at 6 months (P = 0.001) and 12 months (P = 0.002). Figure 2 Open in figure viewer PowerPoint Relationship between total, basal, sleeping, and walking energy expenditure and fat‐free mass in RYGB group and control at baseline and 1.5, 6, and 12 months post‐baseline. Table 3. Energy expenditure, heart rate, and physical activity during 24‐h calorimetry of the RYGB group (n = 11) and controls (n = 5) Post‐baseline Time effect within Baseline 1.5 months 6 months 12 months group (P‐value) Post hoc testa TEE (kcal/day) RYGB 3,189 ± 358b 2,421 ± 243 2,363 ± 256 2,323 ± 294 0.001 ab, ac, ad Control 3,110 ± 512 2,859 ± 374 2,927 ± 421 2,887 ± 575 0.072 PAL RYGB 1.39 ± 0.07 1.30 ± 0.12 1.32 ± 0.08 1.24 ± 0.12 0.001 ab, ad, cd Control 1.36 ± 0.07 1.29 ± 0.07 1.27 ± 0.11 1.27 ± 0.07 0.212 AEE (kcal/day) RYGB 535 ± 111 306 ± 115 309 ± 130 257 ± 118 0.001 ab, ac, ad Control 495 ± 183 332 ± 133 304 ± 221 303 ± 132 0.160 HR (bpm) RYGB 85.8 ± 6.1 71.6 ± 9.5 72.6 ± 3.6 70.5 ± 7.6 0.002 ab, ac, ad Control 84.0 ± 11.6 79.3 ± 12.7 80.1 ± 9.4 77.5 ± 13.1 0.484 Actiheart (counts/day) RYGB 24,202 ± 4,082 20,619 ± 8,099 22,716 ± 7,356 19,839 ± 5,419 0.326 NS Control 29,088 ± 8,200 27,650 ± 5,211 27,187 ± 13,405 22,836 ± 13,178 0.977 BMR (kcal/day) RYGB 2,335 ± 374 1,909 ± 333 1,818 ± 189 1,877 ± 305 0.001 ab, ac, ad Control 2,304 ± 319 2,241 ± 329 2,331 ± 321 2,296 ± 450 0.150 BMR HR (bpm) RYGB 76.6 ± 7.7 64.4 ± 10.3 62.5 ± 5.0 64.9 ± 6.7 0.001 ab, ac, ad Control 73.9 ± 8.1 75.6 ± 8.5 72.3 ± 10.5 71.7 ± 13.0 0.874 Sleep EE (kcal/min) RYGB 1.57 ± 0.21 1.19 ± 0.18 1.17 ± 0.13 1.20 ± 0.16 <0.0001 ab, ac, ad Control 1.52 ± 0.22 1.41 ± 0.20 1.51 ± 0.17 1.49 ± 0.24 0.085 Sleep HR (bpm) RYGB 75.7 ± 7.3 62.0 ± 10.2 61.0 ± 4.6 63.8 ± 7.0 0.002 ab, ac Control 72.2 ± 10.8 71.0 ± 13.4 72.5 ± 9.6 69.8 ± 12.6 0.816 Walking EE at 2.5 mph (kcal/min) RYGB 9.2 ± 2.2 6.6 ± 0.8 6.1 ± 1.8 5.7 ± 1.3 <0.0001 ab, ac, ad Control 8.7 ± 1.1 8.2 ± 1.0 7.7 ± 1.2 9.0 ± 2.0 0.597 Walking HR at 2.5 mph (bpm) RYGB 143 ± 14.0 128 ± 12.3 121 ± 9.7 112 ± 11.1 0.003 ab, ac, ad Control 146 ± 7.0 135 ± 14.3 124 ± 8.6 141 ± 7.7 0.019 ac Energy economy of walking (kcal·kg−1·km−1) RYGB 0.013 ± 0.002 0.010 ± 0.001 0.010 ± 0.001 0.010 ± 0.001 0.001 ab, ad Control 0.013 ± 0.003 0.013 ± 0.002 0.012 ± 0.002 0.012 ± 0.002 0.847 In addition to changes in basal energy requirements, the energy expended in physical activity also declined. AEE declined by 41% and the energy cost of walking decreased by 28% at 1.5 months after surgery (P = 0.001). Adjusted for age, sex, FFM, and FM, postsurgical AEE (kcal/day) and walking EE (kcal/min) were still significantly lower than baseline (P = 0.001‐0.0001; Figure 2). The energy economy of walking [kcal/(kg km)] also decreased at 1.5 months postsurgery (P = 0.001) and persisted at the lower level at 6 and 12 months postsurgery. Substrate utilization was significantly altered in the RYGB group, but not in controls (Table 4). At 1.5 months postsurgery, 24‐h RQ and NPRQ declined sharply, reflective of increased fat utilization and decreased carbohydrate utilization (P = 0.001). Thereafter, the changes in fat and carbohydrate utilization reversed, approaching baseline values. At 1.5 months postsurgery, protein utilization dropped significantly (P = 0.001), but was restored at 6 and 12 months. Adjusted for age, sex, FFM, FM, and energy balance, the time effects for substrate utilization were still significant (P = 0.001‐0.05). Table 4. Substrate utilization during 24‐h calorimetry of the RYGB group (n = 11) and controls (n = 5) Post‐baseline Time effect within Baseline 1.5 months 6 months 12 months group (P‐value) Post hoc testa RQ RYGB 0.85 ± 0.03b 0.76 ± 0.02 0.81 ± 0.03 0.82 ± 0.03 <0.0001 ab, bc, bd Control 0.83 ± 0.02 0.82 ± 0.03 0.81 ± 0.05 0.84 ± 0.04 0.385 Protein utilization (g/day) RYGB 97 ± 43 34 ± 12 70 ± 20 77 ± 12 <0.0001 ab, bc, bd Control 101 ± 21 80 ± 23 70 ± 31 95 ± 28 0.208 Carbohydrate utilization (g/day) RYGB 331 ± 72 94 ± 46 169 ± 48 172 ± 54 <0.0001 ab, ac, ad Control 293 ± 94 222 ± 76 227 ± 144 282 ± 130 0.567 Fat utilization (g/day) RYGB 142 ± 40 197 ± 30 140 ± 35 131 ± 38 0.001 ab, bc, bd, cd Control 149 ± 19 164 ± 44 174 ± 39 133 ± 33 0.352 Protein utilization (%EE) RYGB 14.2 ± 5.3 6.5 ± 2.2 14.2 ± 4.6 16.0 ± 3.6 <0.0001 ab, bd Control 15.5 ± 3.2 13.2 ± 4.0 11.4 ± 5.0 15.5 ± 3.5 0.424 Carbohydrate utilization (%EE) RYGB 43.9 ± 9.9 16.3 ± 8.2 30.0 ± 8.7 31.3 ± 10.2 <0.0001 ab, bc, bd Control 38.6 ± 6.5 32.5 ± 10.4 31.2 ± 17.1 39.8 ± 12.3 0.333 Fat utilization (%EE) RYGB 41.7 ± 9.0 76.8 ± 8.6 55.6 ± 10.9 52.5 ± 11.0 <0.0001 ab, bc, bd Control 45.7 ± 6.5 54.1 ± 12.2 57.1 ± 14.6 44.5 ± 11.8 0.375 NPRQ RYGB 0.85 ± 0.03 0.76 ± 0.02 0.81 ± 0.03 0.81 ± 0.03 <0.0001 ab, bc, bd Control 0.84 ± 0.02 0.81 ± 0.04 0.81 ± 0.05 0.84 ± 0.04 0.375 Carbohydrate utilization (%NPEE) RYGB 51.2 ± 10.9 17.5 ± 8.8 35.3 ± 11.4 37.4 ± 12.2 <0.0001 ab, bc, bd Control 45.7 ± 7.3 37.8 ± 13.1 34.9 ± 17.3 47.2 ± 14.1 0.466 Fat utilization (%NPEE) RYGB 48.8 ± 10.9 82.5 ± 8.8 64.7 ± 11.4 62.6 ± 12.2 <0.0001 ab, bc, bd Control 54.3 ± 7.3 62.2 ± 13.1 65.1 ± 17.3 52.8 ± 14.1 0.456 Mixed‐effects linear regression models adjusted for age, sex, FFM, and FM were used to explore neuroendocrine mechanisms associated with suppressed EE following RYGB surgery (Table 5 and Figure 3). The changes in TEE, BMR, and/or sleep EE were associated with changes in insulin, HOMA, adiponectin, leptin, TSH, total T3, PYY3‐36, GLP2, and urinary NE and E. Substrate utilization was not associated with neuroendocrine alterations; however, fat utilization was positively associated with fasting serum NEFA. Figure 3 Open in figure viewer PowerPoint Changes in total energy expenditure (TEE), basal metabolic rate (BMR), and fasting serum hormones in adolescents at baseline and 1.5, 6, and 12 months postsurgery. Table 5. Associations between energy expenditure and fasting serum hormones and urinary catecholamine excretion in RYGB group (n = 11) TEE BMR Sleep EE HR Independent variable β (SE) P‐value β (SE) P‐value β (SE) P‐value β (SE) P‐value Insulin (μU/ml)a 328 (71) 0.001 204 (68) 0.008 0.14 (0.04) 0.001 7.68 (2.58) 0.008 HOMAa 338 (57) 0.0001 210 (59) 0.002 0.17 (0.03) 0.001 7.88 (2.27) 0.003 Adiponectin (ng/ml)a 372 (149) 0.023 −219 (129) 0.108 −0.18 (0.08) 0.042 −8.2 (5.0) 0.117 Resistin (ng/ml) 18.4 (15.6) 0.253 7.91 (11.4) 0.495 0.01 (0.01) 0.333 0.27 (0.53) 0.615 Leptin (ng/ml) 367 (94) 0.001 127 (80.6) 0.132 0.12 (0.05) 0.043 2.93 (3.17) 0.366 CRP (ng/ml)a 63.5 (39.8) 0.128 28.8 (29.3) 0.338 0.02 (0.02) 0.265 3.61 (0.99) 0.002 TSH (μIU/ml)a 266 (110) 0.027 166 (83) 0.062 0.12 (0.06) 0.056 5.07 (3.80) 0.200 Total T3 (ng/dl) 624 (143) 0.001 497 (119) 0.001 0.33 (0.08) 0.001 13.28 (4.94) 0.015 Total T4 (ng/dl) 189 (248) 0.455 11.1 (179) 0.951 0.08 (0.12) 0.542 11.13 (6.77) 0.118 Free T3 (pg/ml) 188 (99) 0.075 120 (74) 0.124 0.10 (0.05) 0.053 5.5 (2.26) 0.026 Free T4 (ng/dl) 184 (228) 0.431 60.5 (170) 0.726 0.09 (0.12) 0.443 8.92 (4.81) 0.081 Reverse T3 (ng/ml) −1,298 (719) 0.091 −772 (530) 0.165 −0.61 (0.36) 0.109 −8.48 (23.54) 0.724 PYY3‐36 (pg/ml) 5.68 (1.33) 0.001 2.94 (1.38) 0.049 0.002 (0.0007) 0.004 0.16 (0.05) 0.007 GLP1 (pM) −1.79 (2.37) 0.460 −2.04 (1.72) 0.252 −0.0008 (0.001) 0.307 0.12 (0.05) 0.023 GLP2 (ng/ml) 68.5 (16.5) 0.001 60.2 (15.5) 0.001 0.04 (0.01) 0.003 2.24 (0.51) 0.001 Urinary NE (nmol/day) 181.4 (56.5) 0.005 135 (60) 0.037 0.10 (0.03) 0.004 5.74 (1.94) 0.009 Urinary E (nmol/day) 167.4 (54.1) 0.006 116 (70) 0.114 0.07 (0.05) 0.151 2.83 (2.14) 0.201

Discussion Here, we demonstrate that energetic adaptations in response to RYGB surgery in severely obese adolescents 1) are not totally explained by weight, FFM, or FM loss, 2) are associated with changes in insulin, leptin, adiponectin, T3, gut hormones, and SNS activity, and 3) persist 12 months after surgery despite a diminishing rate of weight loss. RYGB‐induced energetic adaptations were observed in TEE and its components after surgery. The majority of the adaptive thermogenesis occurred by 1.5 months after surgery, coincident with the decline in FFM and biochemical changes. TEE, AEE, BMR, sleep EE, and walking EE declined by 24%, 41%, 19%, 24%, and 28% at 1.5 months, and then remained at the suppressed level at 6 and 12 months after surgery. Heart rate paralleled the decline in EE, probably driven by the autonomic nervous system (23). Despite the significant slowing of weight loss by 12 months postsurgery, the presurgical relationship between EE and weight or FFM was not restored. Lower energy economy of walking postsurgically also indicated energy conservation. Within the confines of the calorimeter, AEE and PAL declined in both groups, possibly due to habituation to the room calorimeter at follow‐up. As expected on very low calorie diets, negative energy balance caused a shift toward increased fat oxidation. At 1.5 months after surgery, mean 24‐h RQ was 0.76, and fat utilization had increased markedly to 77% of EE, a finding likely explained best by a shift from the use of exogenous (dietary) energy intake to the use of endogenous fat stores for fuel during the rapid weight loss phase associated with hypocaloric dietary intake early postoperatively. The measurements at 6 and 12 months demonstrated a decrease in fat utilization and an increase in carbohydrate utilization, despite continued fat mass (FM) loss (utilization). As first observed in the Minnesota Experiment by Keys et al. (24), caloric restriction resulted in a reduction in BMR that was greater than that accounted for by the loss in weight and FFM. In these adolescents, RYGB surgery resulted in substantial reductions in weight (30% of initial weight), as in other studies (25), and FM (47% of initial FM) at 12 months postsurgery; however, FFM (12% of initial FFM) appeared to be relatively conserved. FFM loss occurred primarily in the first 1.5 months after surgery, and plateaued thereafter. In these adolescents, the proportion of total weight loss was 22% as FFM, and 78% as FM at 12 months postsurgery. In adults, the proportion of weight loss was 31% as FFM with RYGB surgery (26). The neuroendocrine mechanisms underlying the energetic responses to weight loss induced by RYGB surgery are not well elucidated but may involve insulin, adipokines, thyroid hormones, gut hormones, and SNS activity. Our data demonstrate that decreases in fasting serum insulin, leptin, and T3, gut hormones, and 24‐h urinary excretion of NE parallel the fall in TEE, BMR, and sleep EE and that the effects on EE are statistically independent of FFM and FM losses. After RYGB surgery, there was a rapid improvement in insulin sensitivity associated with changes in total T3, leptin, and adiponectin. The fall in insulin (27) and leptin with weight loss (28) acts to decrease SNS activity (29), thereby lowering BMR independently of changes in weight. The changes in NE likely contribute to the suppressed EE through direct effects on skeletal muscle and indirect effects on thyroid hormones (30). Adipokines (leptin, adiponectin, and resistin) interact both centrally and peripherally to regulate energy intake and EE (28). Leptin can reduce FM centrally through inhibition of appetite, stimulation of thermogenesis, and fat oxidation. In these adolescents, leptin correlated closely with FM loss. Leptin was a strong predictor of the adaptations in TEE, BMR, and sleep EE. We did not observe a significant effect of leptin on substrate utilization. Thyroid hormones, specifically TSH and T3, decreased after RYGB‐induced weight loss in these adolescents. Elevated TSH and T3 levels in obese individuals have been shown to normalize with substantial weight loss (29). The changes in T3 were associated with adaptations in TEE, BMR, and sleep EE, confirming the role of thyroid hormones in the regulation of energy metabolism. A reduction in thyroid activity acts to decrease oxygen consumption, slow cellular metabolism, and conserve energy stores (31). In conventional weight loss, plasma T3 decreased in conjunction with 24‐h TEE (32). The changes in gut hormones after RYGB surgery have been hypothesized to mediate enhanced satiety, whereas the effects on EE are uncertain. In humans, the effects of GLP1 and PYY on EE are emerging but inconsistent (7). PYY was positively correlated with resting EE (33) and negatively correlated in another study (34). The infusion of PYY3‐36 tended to reduce EE in lean and obese adults (35). In our study, fasting PYY3‐36 and GLP2 declined after RYGB surgery and were positively associated with TEE, BMR, and sleep EE. A series of studies explored whether energetic adaptations were a result of caloric restriction during active weight loss or maintenance of a reduced weight after conventional weight loss (6, 23, 30, 36, 37). The maintenance of reduced weight was accompanied by increased skeletal muscle work efficiency and decreased serum T3 and urinary NE excretion (30). Our results corroborate these findings in that energetic adaptations were not observed in controls subjected to acute caloric restriction during 24‐h calorimetry, and TEE and its components remained suppressed after RYGB‐induced weight loss plateaued at 12 months. Controversy exists over the persistence of energetic adaptations after weight loss (7, 10, 36, 38). The suppression of TEE, BMR, sleep EE, AEE, and walking EE observed in these adolescents after RYGB surgery clearly persisted, despite the fact that weight loss had plateaued in most cases. In 12 adults undergoing RYGB surgery, TEE and sleep EE were reduced at 6 months and persisted at 12 months (8). In another study, patients who regained weight 2 years after RYGB surgery had lower resting EE (39). After conventional weight loss, a disproportionate reduction in EE persisted in individuals who maintained a body weight reduction of ≥10% for greater than 1 year (6). RYGB surgery, when used for appropriate patients, clearly can afford substantial health benefits for extremely obese adolescents. This study demonstrated that RYGB surgery not only improved insulin sensitivity, decreased heart rate, and reduced inflammation but also induced persistent energetic, metabolic, and endocrine adaptations that favor weight regain. The elucidation of these adaptations induced by weight loss after RYGB surgery will be instrumental in guiding the clinical management of these patients to prevent recidivism and future research into alternate surgical and nonsurgical treatments for morbid obesity.