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Exercise training and diet-induced weight loss increase markers of hepatic bile acid (BA) synthesis and reduce serum total BA concentrations in obese women.
Mercer, KE, Maurer, A, Pack, LM, Ono-Moore, K, Spray, BJ, Campbell, C, Chandler, CJ, Burnett, D, Souza, E, Casazza, G, et al
American journal of physiology. Endocrinology and metabolism. 2021;(5):E864-E873
Abstract
Regular exercise has profound metabolic influence on the liver, but effects on bile acid (BA) metabolism are less well known. BAs are synthesized exclusively in the liver from cholesterol via the rate-limiting enzyme cholesterol 7 alpha-hydroxylase (CYP7A1). BAs contribute to the solubilization and absorption of lipids and serve as important signaling molecules, capable of systemic endocrine function. Circulating BAs increase with obesity and insulin resistance, but effects following exercise and diet-induced weight loss are unknown. To test if improvements in fitness and weight loss as a result of exercise training enhance BA metabolism, we measured serum concentrations of total BAs (conjugated and unconjugated primary and secondary BAs) in sedentary, obese, insulin-resistant women (N = 11) before (PRE) and after (POST) a ∼14-wk exercise and diet-induced weight loss intervention. BAs were measured in serum collected after an overnight fast and during an oral glucose tolerance test (OGTT). Serum fibroblast growth factor 19 (FGF19; a regulator of BA synthesis) and 7-alpha-hydroxy-cholesten-3-one (C4, a marker of CYP7A1 enzymatic activity) also were measured. Using linear mixed-model analyses and the change in V̇O2peak (mL/min/kg) as a covariate, we observed that exercise and weight loss intervention decreased total fasting serum BA by ∼30% (P = 0.001) and increased fasting serum C4 concentrations by 55% (P = 0.004). C4 was significantly correlated with serum total BAs only in the POST condition, whereas serum FGF19 was unchanged. These data indicate that a fitness and weight loss intervention modifies BA metabolism in obese women and suggest that improved metabolic health associates with higher postabsorptive (fasting) BA synthesis. Furthermore, pre- vs. postintervention patterns of serum C4 following an OGTT support the hypothesis that responsiveness of BA synthesis to postprandial inhibition is improved after exercise and weight loss.NEW & NOTEWORTHY Exercise and weight loss in previously sedentary, insulin-resistant women facilitates a significant improvement in insulin sensitivity and fitness that may be linked to changes in bile acid metabolism. Diet-induced weight loss plus exercise-induced increases in fitness promote greater postabsorptive bile acid synthesis while also sensitizing the bile acid metabolic system to feedback inhibition during a glucose challenge when glucose and insulin are elevated.
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The gene variant rs2419621 of ACYL-CoA synthetase long-chain 5 gene is associated with weight loss and metabolic changes in response to a robotic sleeve gastrectomy in morbid obese subjects.
de Luis, D, Izaola, O, Primo, D, Pacheco, D
European review for medical and pharmacological sciences. 2021;(22):7037-7043
Abstract
OBJECTIVE Genetic mechanisms have been involved in the pathogenesis of obesity and weight loss due to bariatric surgery. The aim of our work was to evaluate the effects of rs2419621 genetic variant of ACSL5 gene on weight and metabolic changes after a robotic sleeve gastrectomy. PATIENTS AND METHODS 48 patients were enrolled. Comorbidities, biochemical and anthropometric parameters evaluation were registered before and after 3, 6 and 12 months follow up. Genotype of rs2419621 ACSL5 gene was evaluated. RESULTS We classified the subjects with a dominant model, in two groups: those carriers T allele (TT+CT, 37.5%) and non-carriers T allele (CC, 62.5%). We reported a statistically significant reduction of body weight, waist circumference, percentage of excess of weight loss (EWL%), blood pressure, glucose, insulin, LDL-cholesterol and triglycerides after surgery. After 12 months, delta of (EWL%; 70.1% vs. 64,2%; p=0.04), weight (40.7+4.1 kg vs. 32.5+4.8 kg; p=0.03), waist circumference (29.1+3.1 cm vs. 22.2+2.8 kg; p=0.02) and triglycerides (51.2+9.1 mg/dl vs. 32.1+8.1; p=0.02) were higher in T allele carriers than non-T allele carriers. All comorbidities improved, but the percentage of patients with hypertriglyceridemia diminished early in the 3-month follow-up in the T-allele carriers, and at 12 months, no patient with the T allele had hypertriglyceridemia. CONCLUSIONS Our data showed that the genetic variant (rs2419621) of ACSL5 gene are associated with better improvement of adiposity and triglyceride levels in subjects with T allele, after a robotic sleeve gastrectomy.
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Effect of Subcutaneous Semaglutide vs Placebo as an Adjunct to Intensive Behavioral Therapy on Body Weight in Adults With Overweight or Obesity: The STEP 3 Randomized Clinical Trial.
Wadden, TA, Bailey, TS, Billings, LK, Davies, M, Frias, JP, Koroleva, A, Lingvay, I, O'Neil, PM, Rubino, DM, Skovgaard, D, et al
JAMA. 2021;(14):1403-1413
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IMPORTANCE Weight loss improves cardiometabolic risk factors in people with overweight or obesity. Intensive lifestyle intervention and pharmacotherapy are the most effective noninvasive weight loss approaches. OBJECTIVE To compare the effects of once-weekly subcutaneous semaglutide, 2.4 mg vs placebo for weight management as an adjunct to intensive behavioral therapy with initial low-calorie diet in adults with overweight or obesity. DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind, parallel-group, 68-week, phase 3a study (STEP 3) conducted at 41 sites in the US from August 2018 to April 2020 in adults without diabetes (N = 611) and with either overweight (body mass index ≥27) plus at least 1 comorbidity or obesity (body mass index ≥30). INTERVENTIONS Participants were randomized (2:1) to semaglutide, 2.4 mg (n = 407) or placebo (n = 204), both combined with a low-calorie diet for the first 8 weeks and intensive behavioral therapy (ie, 30 counseling visits) during 68 weeks. MAIN OUTCOMES AND MEASURES The co-primary end points were percentage change in body weight and the loss of 5% or more of baseline weight by week 68. Confirmatory secondary end points included losses of at least 10% or 15% of baseline weight. RESULTS Of 611 randomized participants (495 women [81.0%], mean age 46 years [SD, 13], body weight 105.8 kg [SD, 22.9], and body mass index 38.0 [SD, 6.7]), 567 (92.8%) completed the trial, and 505 (82.7%) were receiving treatment at trial end. At week 68, the estimated mean body weight change from baseline was -16.0% for semaglutide vs -5.7% for placebo (difference, -10.3 percentage points [95% CI, -12.0 to -8.6]; P < .001). More participants treated with semaglutide vs placebo lost at least 5% of baseline body weight (86.6% vs 47.6%, respectively; P < .001). A higher proportion of participants in the semaglutide vs placebo group achieved weight losses of at least 10% or 15% (75.3% vs 27.0% and 55.8% vs 13.2%, respectively; P < .001). Gastrointestinal adverse events were more frequent with semaglutide (82.8%) vs placebo (63.2%). Treatment was discontinued owing to these events in 3.4% of semaglutide participants vs 0% of placebo participants. CONCLUSIONS AND RELEVANCE Among adults with overweight or obesity, once-weekly subcutaneous semaglutide compared with placebo, used as an adjunct to intensive behavioral therapy and initial low-calorie diet, resulted in significantly greater weight loss during 68 weeks. Further research is needed to assess the durability of these findings. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03611582.
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Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial.
Rubino, D, Abrahamsson, N, Davies, M, Hesse, D, Greenway, FL, Jensen, C, Lingvay, I, Mosenzon, O, Rosenstock, J, Rubio, MA, et al
JAMA. 2021;(14):1414-1425
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IMPORTANCE The effect of continuing vs withdrawing treatment with semaglutide, a glucagon-like peptide 1 receptor agonist, on weight loss maintenance in people with overweight or obesity is unknown. OBJECTIVE To compare continued once-weekly treatment with subcutaneous semaglutide, 2.4 mg, with switch to placebo for weight maintenance (both with lifestyle intervention) in adults with overweight or obesity after a 20-week run-in with subcutaneous semaglutide titrated to 2.4 mg weekly. DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind, 68-week phase 3a withdrawal study conducted at 73 sites in 10 countries from June 2018 to March 2020 in adults with body mass index of at least 30 (or ≥27 with ≥1 weight-related comorbidity) and without diabetes. INTERVENTIONS A total of 902 participants received once-weekly subcutaneous semaglutide during run-in. After 20 weeks (16 weeks of dose escalation; 4 weeks of maintenance dose), 803 participants (89.0%) who reached the 2.4-mg/wk semaglutide maintenance dose were randomized (2:1) to 48 weeks of continued subcutaneous semaglutide (n = 535) or switched to placebo (n = 268), plus lifestyle intervention in both groups. MAIN OUTCOMES AND MEASURES The primary end point was percent change in body weight from week 20 to week 68; confirmatory secondary end points were changes in waist circumference, systolic blood pressure, and physical functioning (assessed using the Short Form 36 Version 2 Health Survey, Acute Version [SF-36]). RESULTS Among 803 study participants who completed the 20-week run-in period (with a mean weight loss of 10.6%) and were randomized (mean age, 46 [SD, 12] years; 634 [79%] women; mean body weight, 107.2 kg [SD, 22.7 kg]), 787 participants (98.0%) completed the trial and 741 (92.3%) completed treatment. With continued semaglutide, mean body weight change from week 20 to week 68 was -7.9% vs +6.9% with the switch to placebo (difference, -14.8 [95% CI, -16.0 to -13.5] percentage points; P < .001). Waist circumference (-9.7 cm [95% CI, -10.9 to -8.5 cm]), systolic blood pressure (-3.9 mm Hg [95% CI, -5.8 to -2.0 mm Hg]), and SF-36 physical functioning score (2.5 [95% CI, 1.6-3.3]) also improved with continued subcutaneous semaglutide vs placebo (all P < .001). Gastrointestinal events were reported in 49.1% of participants who continued subcutaneous semaglutide vs 26.1% with placebo; similar proportions discontinued treatment because of adverse events with continued semaglutide (2.4%) and placebo (2.2%). CONCLUSIONS AND RELEVANCE Among adults with overweight or obesity who completed a 20-week run-in period with subcutaneous semaglutide, 2.4 mg once weekly, maintaining treatment with semaglutide compared with switching to placebo resulted in continued weight loss over the following 48 weeks. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03548987.
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Infancy and Childhood Obesity Grade Predicts Weight Loss in Adulthood: The ONTIME Study.
Morales, E, Torres-Castillo, N, Garaulet, M
Nutrients. 2021;(7)
Abstract
We examined the relationships between intergenerational obesity, weight and size at birth, and obesity from infancy to adolescence with weight loss in response to a dietary intervention. We studied 4264 participants (3369 women; mean age 41.5 ± 12.9 years) of the ONTIME study. Participants followed a weight-loss treatment based on a Mediterranean diet. Associations between grandparental and parental obesity grade, birth weight and size, and obesity grade in infancy, childhood and adolescence with total weight loss in response to treatment were assessed, using multivariate linear regression models. A lower weight loss (kg) in response to treatment was found among participants who were obese during infancy (beta coefficient -2.13 kg; 95% CI, -3.96, -0.30; p = 0.023). Furthermore, obesity during infancy and also during childhood was associated with a slower weekly rate of weight loss during treatment (p < 0.05). In conclusion, obesity in infancy and in childhood impairs the weight-loss response to dietary treatments in adulthood. Tackling obesity throughout early life may improve the effectiveness of weight-loss interventions in adulthood.
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Laparoscopic sleeve gastrectomy improves brain connectivity in obese patients.
Hu, Y, Ji, G, Li, G, Zhang, W, Wang, J, Lv, G, He, Y, Yuan, K, von Deneen, KM, Chen, A, et al
Journal of neurology. 2020;(7):1931-1940
Abstract
OBJECTIVE Obese individuals have shown functional abnormalities in frontal-limbic regions, and bariatric surgery is an effective treatment for morbid obesity. The aim of the study was to investigate how bariatric surgery modulates brain regional activation and functional connectivity (FC) to food cues, and whether the underlying structural connectivity (SC) alterations contribute to these functional changes as well as behavioral changes. METHODS A functional magnetic resonance imaging cue-reactivity task with high- (HiCal) and low-calorie (LoCal) food pictures and diffusion tensor imaging (DTI) with deterministic tractography were used to investigate brain reactivity, FC and SC in 28 obese participants tested before and 1 month after laparoscopic sleeve gastrectomy (LSG). Twenty-two obese controls (Ctr) without surgery were also tested at baseline and 1 month later. RESULTS LSG significantly decreased right dorsolateral prefrontal cortex (DLPFC) activation to HiCal versus LoCal cues and increased FC between DLPFC and ventral anterior cingulate cortex (vACC), which are regions involved in self-regulation of feeding behaviors. LSG also increased SC between DLPFC and ACC as quantified by fractional anisotropy. Increases in SC and FC between DLPFC and ACC were associated with greater reductions in BMI, and SC changes were positively correlated with FC changes. Increased SC between right DLPFC and ACC mediated the relationship between reduced BMI and increased right DLPFC-vACC FC; likewise, increases in right DLPFC-vACC FC mediated the relationship between increased right DLPFC-ACC SC and reduced BMI. CONCLUSION LSG might induce weight loss in part by increasing SC and FC between DLPFC and ACC, and thus strengthening top-down control over food intake.
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DNA methylation signature in blood mirrors successful weight-loss during lifestyle interventions: the CENTRAL trial.
Keller, M, Yaskolka Meir, A, Bernhart, SH, Gepner, Y, Shelef, I, Schwarzfuchs, D, Tsaban, G, Zelicha, H, Hopp, L, Müller, L, et al
Genome medicine. 2020;(1):97
Abstract
BACKGROUND One of the major challenges in obesity treatment is to explain the high variability in the individual's response to specific dietary and physical activity interventions. With this study, we tested the hypothesis that specific DNA methylation changes reflect individual responsiveness to lifestyle intervention and may serve as epigenetic predictors for a successful weight-loss. METHODS We conducted an explorative genome-wide DNA methylation analysis in blood samples from 120 subjects (90% men, mean ± SD age = 49 ± 9 years, body mass-index (BMI) = 30.2 ± 3.3 kg/m2) from the 18-month CENTRAL randomized controlled trial who underwent either Mediterranean/low-carbohydrate or low-fat diet with or without physical activity. RESULTS Analyses comparing male subjects with the most prominent body weight-loss (responders, mean weight change - 16%) vs. non-responders (+ 2.4%) (N = 10 each) revealed significant variation in DNA methylation of several genes including LRRC27, CRISP2, and SLFN12 (all adj. P < 1 × 10-5). Gene ontology analysis indicated that biological processes such as cell adhesion and molecular functions such as calcium ion binding could have an important role in determining the success of interventional therapies in obesity. Epigenome-wide association for relative weight-loss (%) identified 15 CpGs being negatively correlated with weight change after intervention (all combined P < 1 × 10- 4) including new and also known obesity candidates such as NUDT3 and NCOR2. A baseline DNA methylation score better predicted successful weight-loss [area under the curve (AUC) receiver operating characteristic (ROC) = 0.95-1.0] than predictors such as age and BMI (AUC ROC = 0.56). CONCLUSIONS Body weight-loss following 18-month lifestyle intervention is associated with specific methylation signatures. Moreover, methylation differences in the identified genes could serve as prognostic biomarkers to predict a successful weight-loss therapy and thus contribute to advances in patient-tailored obesity treatment.
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A Community-Based Feasibility Study of Weight-Loss in Rural, Older Adults with Obesity.
Batsis, JA, Petersen, CL, Cook, SB, Al-Nimr, RI, Pidgeon, D, Mackenzie, TA, Bartels, SJ
Journal of nutrition in gerontology and geriatrics. 2020;(3-4):192-204
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This study was a 12-week feasibility weight-loss intervention consisting of caloric restriction and aerobic/resistance exercise in older adults with obesity (body mass index ≥ 30 kg/m2) in a geographically isolated area. Primary outcomes assessed weight and physical function. Mean age was 71.0 ± 5.1 years (67% female). Individuals completed 100% of all assessments, attended 88% of the physical therapy classes and 89% of the nutrition sessions. Level of satisfaction (5-point Likert) was high (5.0, 1 - low; 5 - high). Weight decreased from 93.7 ± 9.7 to 89.4 ± 4.0 kg (p < 0.001). Mean BMI and waist circumference decreased, respectively, from 35.4 ± 3.4 to 33.6 ± 3.7 (p < 0.001), and 116.3 ± 7.5 to 108.7 ± 9.2 cm (p = 0.002). Grip strength, gait speed, and 5-times sit-to-stand time all improved from 29.2 ± 7.5 to 35.2 ± 6.7 kg (p = 0.006), 1.16 ± 0.21 to 1.35 ± 0.23 m/s (p = 0.004), and 12.5 ± 4.0 to 9.6 ± 1.7s (p = 0.02). The intervention was feasible and acceptable, and holds promise in promoting weight loss with a concomitant improvement in physical function in older adults.
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Reductions in body weight and insulin resistance are not associated with changes in grey matter volume or cortical thickness during the PREVIEW study.
Drummen, M, Heinecke, A, Dorenbos, E, Vreugdenhil, A, Raben, A, Westerterp-Plantenga, MS, Adam, TC
Journal of the neurological sciences. 2019;:106-111
Abstract
INTRODUCTION The effect of changes in body weight or insulin resistance on grey matter volume and cortical thickness change are unclear. The present observational study assessed effects of an 8-week weight loss period (≥8% of body weight), and a subsequent 22-month weight maintenance period on grey matter volume and cortical thickness. METHODS A total of 24 participants (12f/12 m; age 52.8 ± 10.6 years) with overweight/obesity and pre-diabetes were recruited. T1-weighted magnetic resonance imaging was used to determine grey matter volume and cortical thickness at baseline, after the weight loss period and after a medium to high dietary protein weight maintenance period. RESULTS At baseline, global grey matter volume was inversely associated with HOMA-IR, adjusted for sex and age (r = -0.42; p = .049). During the weight loss period participants decreased their BMI (32.1 ± 3.3 to 28.1 ± 2.8 kg/m2, p < .01), body-fat (41.6 ± 6.4 to 35.0 ± 8.0%, p < .01) and insulin resistance (HOMA-IR: 4.0 ± 2.0 to 1.8 ± 0.9, p < .01). During the 22-month weight maintenance period, these parameters gradually increased again (BMI: 29.3 ± 3.8 kg/m2; body-fat: 37.8 ± 9.3%; HOMA-IR: 2.9 ± 1.4, p < .01). Global grey matter volume and cortical thickness did not change significantly during the weight loss or weight maintenance period. Changes in body weight, body-fat percentage or insulin sensitivity were not associated with changes in global grey matter volume. CONCLUSION In conclusion, we confirmed that global grey brain matter volume was inversely associated with insulin resistance at baseline, yet an intervention yielding a decrease in insulin resistance did not lead to changes in global grey brain matter volume or cortical thickness. TRIAL REGISTRATION The trial is registered with ClinicalTrials.gov, NCT01777893.
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Long-term Weight Loss Maintenance in the Continuation of a Randomized Diabetes Prevention Translational Study: The Healthy Living Partnerships to Prevent Diabetes (HELP PD) Continuation Trial.
Vitolins, MZ, Blackwell, CS, Katula, JA, Isom, SP, Case, LD
Diabetes care. 2019;(9):1653-1660
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OBJECTIVE HELP PD was a clinical trial of 301 adults with prediabetes. Participants were randomized to enhanced usual care (EUC) or to a lifestyle weight loss (LWL) intervention led by community health workers that consisted of a 6-month intensive phase (phase 1) and 18 months of maintenance (phase 2). At 24 months, participants were asked to enroll in phase 3 to assess whether continued group maintenance (GM) sessions would maintain improvements realized in phases 1 and 2 compared with self-directed maintenance (SM) or EUC. RESEARCH DESIGN AND METHODS In phase 3, LWL participants were randomly assigned to GM or SM. EUC participants remained in the EUC arm and, along with participants in SM, received monthly newsletters. All participants received semiannual dietitian sessions. Anthropometrics and biomarkers were assessed every 6 months. Mixed-effects models were used to assess changes in outcomes over time. RESULTS Eighty-two of the 151 intervention participants (54%) agreed to participate in phase 3; 41 were randomized to GM and 41 to SM. Of the 150 EUC participants, 107 (71%) continued. Ninety percent of clinic visits were completed. Over 48 months of additional follow-up, outcomes remained relatively stable in the EUC participants; the GM group was able to maintain body weight, BMI, and waist circumference; and these measures all increased significantly (P < 0.001) in the SM group. CONCLUSIONS Participants in the GM arm maintained weight loss achieved in phases 1 and 2, while those in the SM arm regained weight. Because group session attendance by the participants in the GM arm was low, it is unclear what intervention components led to successful weight maintenance.