Lifestyle-induced Weight Loss Research Articles

Reversal of insulin resistance in people with obesity by lifestyle-induced weight loss does not impact the proportion of circulating 12Α-hydroxylated bile acids

Reversal of insulin resistance in people with obesity by lifestyle-induced weight loss does not impact the proportion of circulating 12Α-hydroxylated bile acids

Lifestyle-induced Weight Loss Improves Adipogenic Potential Of Preadipocytes In Females With Different Onsets Of Obesity

Lifestyle-induced Weight Loss Improves Adipogenic Potential Of Preadipocytes In Females With Different Onsets Of Obesity

Reversal of insulin resistance in people with obesity by lifestyle-induced weight loss does not impact the proportion of circulating 12α-hydroxylated bile acids.

Bile acids (BAs) are implicated in the pathogenesis of several metabolic syndrome-related diseases, including insulin resistance (IR) and type 2 diabetes (T2D). It has been reported that IR and T2D are associated with an increased ratio of 12α/non-12α-hydroxylated BAs in the circulating BA pool. It is, however, unknown whether the improvement of insulin sensitivity inversely affects BA composition in humans. Therefore, we assessed whether lifestyle-induced weight loss induces changes in BA metabolism in people with obesity, with or without T2D, and if these changes are associated with metabolic parameters. Individual BAs and C4 were quantified by ultra-high-performance liquid chromatography-tandem mass spectrometry in plasma samples collected from two cohorts of people with obesity (OB) and with T2D and obesity (T2D), before and after a lifestyle intervention. Lifestyle-induced weight loss improved glycaemic control in both cohorts, with plasma BA concentrations not affected by the lifestyle interventions. The ratio of 12α/non-12α-hydroxylated BAs remained unchanged in OB (p = .178) and even slightly increased upon intervention in T2D (p = .0147). Plasma C4 levels were unaffected in OB participants (p = .20) but significantly reduced in T2D after intervention (p = .0003). There were no significant correlations between the ratio of 12α/non-12α-hydroxylated BAs and glucose, insulin, or homeostatic model assessment-IR, nor in plasma triglycerides, low-density lipoprotein cholesterol, lipoprotein (a) in the T2D cohort. Lifestyle-induced weight loss did improve glycaemic control but did not affect BA concentrations. Improvements in insulin sensitivity were not associated with changes in BA parameters in people with obesity, with or without T2D.

Physical Activity and Weight Loss Among Adults With Type 2 Diabetes and Overweight or Obesity

Prior findings from the Look AHEAD trial showed no significant reduction in the risk of cardiovascular events by lifestyle-induced weight loss among individuals with type 2 diabetes (T2D) and overweight or obesity. However, physical activity (PA) may modify the changes in cardiovascular risk associated with weight loss. To examine the joint association of weight loss and PA with the risk of adverse cardiovascular events in patients with T2D and overweight or obesity. This cohort study was a post hoc analysis of the Look AHEAD randomized clinical trial, which compared the cardiovascular effects of weight loss by intensive lifestyle intervention vs diabetes support and education among individuals with T2D and overweight or obesity. The study was conducted from June 2001 to September 2012, and participants were patients in the substudy of accelerometry-measured PA from 8 locations in the United States. Data were analyzed from June to August 2023. Body weight change and accelerometer-derived PA volume across the first 4 years. The primary outcome was a composite cardiovascular outcome including cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina. Among a total of 1229 participants (mean [SD] age, 60 [7] years; 533 male [43%]), 333 (27%) achieved and maintained weight loss for the first 4 years. Among the individuals who maintained weight loss, 105 (32%) maintained high PA volume. During a median of 9.5 years of follow-up, 198 participants (16.1%) experienced the primary outcome. Compared with those with low PA volume and no weight loss (105 [15.8%]), maintaining high PA volume and weight loss was associated with a 61% lower risk of the primary end point (hazard ratio, 0.39; 95% CI, 0.19-0.81; P = .01). However, there was no significant difference in the risk of the primary end point among those with either weight loss only or high PA only. The multiplicative interaction between weight loss and PA for the risk of cardiovascular events was also significant (P for interaction = .01). In this cohort study, maintaining weight loss and higher PA volume was associated with a lower risk of the composite cardiovascular outcome. The findings suggest that the cardiovascular benefits of PA may vary and be enhanced by weight loss among individuals with T2D and overweight or obesity.

Vertebrae but not femur marrow fat transiently decreases in response to body weight loss in an 18-month randomized control trial.

Increased levels of bone marrow adipose tissue (BMAT) are negatively associated with skeletal health and hematopoiesis. BMAT is known to increase with age; however, the effect of long-term weight loss on BMAT is still unknown. In this study, we examined BMAT response to lifestyle-induced weight loss in 138 participants (mean age 48 y; mean body mass index 31kg/m2), who participated in the CENTRAL-MRI trial. Participants were randomized for dietary intervention of low-fat or low-carb, with or without physical activity. Magnetic resonance imaging (MRI) was used to quantify BMAT and other fat depots at baseline, six and eighteen months of intervention. Blood biomarkers were also measured at the same time points. At baseline, the L3 vertebrae BMAT is positively associated with age, HDL cholesterol, HbA1c and adiponectin; but not with other fat depots or other metabolic markers tested. Following six months of dietary intervention, the L3 BMAT declined by an average of 3.1%, followed by a return to baseline after eighteen months (p<0.001 and p=0.189 compared to baseline, respectively). The decrease of BMAT during the first six months was associated with a decrease in waist circumference, cholesterol, proximal-femur BMAT, and superficial subcutaneous adipose tissue (SAT), as well as with younger age. Nevertheless, BMAT changes did not correlate with changes in other fat depots. We conclude that physiological weight loss can transiently reduce BMAT in adults, and this effect is more prominent in younger adults. Our findings suggest that BMAT storage and dynamics are largely independent of other fat depots or cardio-metabolic risk markers, highlighting its unique functions.

Uric acid is elevated in children with obesity and decreased after a lifestyle-induced weight loss intervention.

The International Journal of Integrated Care (IJIC) is an online, open-access, peer-reviewed scientific journal that publishes original articles in the field of integrated care on a continuous basis.IJIC has an Impact Factor of 2.913 (2021 JCR, received in June 2022)The IJIC 20th Anniversary Issue was published in 2021.

The Extent of Lifestyle-Induced Weight Loss Determines the Risk of Prediabetes and Metabolic Syndrome Recurrence during a 5-Year Follow-Up.

It is controversial whether lifestyle-induced weight loss (LIWL) intervention provides long-term benefit. Here, we investigated whether the degree of weight loss (WL) in a controlled LIWL intervention study determined the risk of prediabetes and recurrence of metabolic syndrome (MetS) during a 5-year follow-up. Following LIWL, 58 male participants (age 45–55 years) were divided into four quartiles based on initial WL: Q1 (WL 0–8.1%, n = 15), Q2 (WL 8.1–12.8%, n = 14), Q3 (WL 12.8–16.0%, n = 14), and Q4 (WL 16.0–27.5%, n = 15). We analyzed changes in BMI, HDL cholesterol, triglycerides (TGs), blood pressure, and fasting plasma glucose (FPG) at annual follow-up visits. With a weight gain after LIWL between 1.2 (Q2) and 2.5 kg/year (Q4), the reduction in BMI was maintained for 4 (Q2, p = 0.03) or 5 (Q3, p = 0.03; Q4, p < 0.01) years, respectively, and an increase in FPG levels above baseline values was prevented in Q2–Q4. Accordingly, there was no increase in prediabetes incidence after LIWL in participants in Q2 (up to 2 years), Q3 and Q4 (up to 5 years). A sustained reduction in MetS was maintained in Q4 during the 5-year follow-up. The present data indicate that a greater initial LIWL reduces the risk of prediabetes and recurrence of MetS for up to 5 years.

Impact of Obesity on Response to Biologic Therapies in Patients with Inflammatory Bowel Diseases.

Approximately 20-40% of patients with inflammatory bowel disease (IBD) are obese. Obesity is associated with inferior outcomes in patients with IBD, with lower rates of achieving remission, poor quality of life, and higher burden of unplanned healthcare utilization. Multiple cohort studies in patients with immune-mediated inflammatory diseases, including IBD, treated with biologic agents like tumor necrosis factor-α antagonists have suggested that obesity is associated with inferior response to biologic therapy. This may be related to the negative impact of obesity on thepharmacokinetics of biologic agents.Pharmacokinetic studies of multiple biologic agents have demonstrated that high body weight is associated with more rapid clearance and a higher volume of distribution of biologic agents, which leads to low trough concentrations. Randomized trials in patients with psoriasis and psoriatic arthritis treated with biologic agents suggest that diet- or lifestyle-induced weight loss is associated with improved response to therapy. This provides an opportunity to explore intentional weight loss as adjunctive therapy in obese patients with IBD. However, diet and lifestyle interventions for weight loss are hard to implement in patients with IBD; hence, long-term therapy with weight-loss agents (such as with phentermine-topiramate, naltrexone-bupropion) is attractive as adjunctive therapy in obese patients with IBD.

Dose-response relationship between weight loss and improvements in obstructive sleep apnea severity after a diet/lifestyle interventions: secondary analyses of the "MIMOSA" randomized clinical trial.

Lifestyle-induced weight loss is a complementary therapeutic approach for obstructive sleep apnea (OSA). We aimed at identifying the dose-response relationship between weight loss and OSA severity improvement. This is a secondary analysis of a 6-month clinical trial in 180 adult, overweight/obese moderate-to-severe OSA patients. Participants were randomized to a standard care, a Mediterranean diet, or a Mediterranean lifestyle arm. All patients were prescribed with continuous positive airway pressure (CPAP), while intervention arms additionally participated in a weight-loss dietary/lifestyle intervention. Based on percent change in weight at 6 months, participants were categorized into a weight-stable/gain (WS/GG) group or 3 weight-loss groups (WLG): < 5%WLG, 5%-10%WLG, and ≥ 10%WLG. Polysomnographic data and OSA symptoms were evaluated preintervention and postintervention. Respiratory events and oximetry indices improved only in patients who lost weight and improvements were proportional to the degree of weight loss. Median percent change in apnea-hypopnea index (AHI) was -11.7%, - 37.9%, and - 49.3% in the < 5%WLG, 5%-10%WLG, and ≥ 10%WLG, respectively (P < .001). Compared to the WS/GG, the age-, sex-, baseline-, and CPAP use-adjusted relative risk (95% confidence interval) of severe OSA (AHI ≥ 30 events/h) was 0.45 (0.23-0.87) in the 5%-10%WLG and 0.32 (0.17-0.64) in the ≥ 10%WLG; the risk was also lower in the ≥ 10%WLG vs the < 5%WLG (0.42 [0.22-0.82]). Insomnia and daytime sleepiness also improved more in participants exhibiting ≥ 5% weight loss. Even a < 5% weight loss can reduce respiratory events, but a ≥ 5% and ideally ≥ 10% weight loss is necessary for reducing the prevalence of severe OSA. Registry: ClinicalTrials.gov; Name: Mediterranean Diet/Lifestyle Intervention in Obstructive Sleep Apnea; URL: https://clinicaltrials.gov/ct2/show/NCT02515357; Identifier: NCT02515357. Georgoulis M, Yiannakouris N, Kechribari I, etal. Dose-response relationship between weight loss and improvements in obstructive sleep apnea severity after a diet/lifestyle intervention: secondary analyses of the "MIMOSA" randomized clinical trial. J Clin Sleep Med. 2022;18(5):1251-1261.

Osteocalcin Is Independently Associated with C-Reactive Protein during Lifestyle-Induced Weight Loss in Metabolic Syndrome.

Bone-derived osteocalcin has been suggested to be a metabolic regulator. To scrutinize the relation between osteocalcin and peripheral insulin sensitivity, we analyzed changes in serum osteocalcin relative to changes in insulin sensitivity, low-grade inflammation, and bone mineral density following lifestyle-induced weight loss in individuals with metabolic syndrome (MetS). Participants with MetS were randomized to a weight loss program or to a control group. Before and after the 6-month intervention period, clinical and laboratory parameters and serum osteocalcin levels were determined. Changes in body composition were analyzed by dual-energy X-ray absorptiometry (DXA). In participants of the intervention group, weight loss resulted in improved insulin sensitivity and amelioration of inflammation. Increased serum levels of osteocalcin correlated inversely with BMI (r = −0.63; p < 0.001), total fat mass (r = −0.58, p < 0.001), total lean mass (r = −0.45, p < 0.001), C-reactive protein (CRP) (r = −0.37; p < 0.01), insulin (r = −0.4; p < 0.001), leptin (r = −0.53; p < 0.001), triglycerides (r = −0.42; p < 0.001), and alanine aminotransferase (ALAT) (r = −0.52; p < 0.001). Regression analysis revealed that osteocalcin was independently associated with changes in CRP but not with changes in insulin concentration, fat mass, or bone mineral density, suggesting that weight loss-induced higher serum osteocalcin is primarily associated with reduced inflammation.

Fecal Metaproteomics Reveals Reduced Gut Inflammation and Changed Microbial Metabolism Following Lifestyle-Induced Weight Loss.

Gut microbiota-mediated inflammation promotes obesity-associated low-grade inflammation, which represents a hallmark of metabolic syndrome. To investigate if lifestyle-induced weight loss (WL) may modulate the gut microbiome composition and its interaction with the host on a functional level, we analyzed the fecal metaproteome of 33 individuals with metabolic syndrome in a longitudinal study before and after lifestyle-induced WL in a well-defined cohort. The 6-month WL intervention resulted in reduced BMI (−13.7%), improved insulin sensitivity (HOMA-IR, −46.1%), and reduced levels of circulating hsCRP (−39.9%), indicating metabolic syndrome reversal. The metaprotein spectra revealed a decrease of human proteins associated with gut inflammation. Taxonomic analysis revealed only minor changes in the bacterial composition with an increase of the families Desulfovibrionaceae, Leptospiraceae, Syntrophomonadaceae, Thermotogaceae and Verrucomicrobiaceae. Yet we detected an increased abundance of microbial metaprotein spectra that suggest an enhanced hydrolysis of complex carbohydrates. Hence, lifestyle-induced WL was associated with reduced gut inflammation and functional changes of human and microbial enzymes for carbohydrate hydrolysis while the taxonomic composition of the gut microbiome remained almost stable. The metaproteomics workflow has proven to be a suitable method for monitoring inflammatory changes in the fecal metaproteome.

Gene expression profile of CD14+ blood monocytes following lifestyle-induced weight loss in individuals with metabolic syndrome

Lifestyle-induced weight loss is regarded as an efficient therapy to reverse metabolic syndrome (MetS) and to prevent disease progression. The objective of this study was to investigate whether lifestyle-induced weight loss modulates gene expression in circulating monocytes. We analyzed and compared gene expression in monocytes (CD14+ cells) and subcutaneous adipose tissue biopsies by unbiased mRNA profiling. Samples were obtained before and after diet-induced weight loss in well-defined male individuals in a prospective controlled clinical trial (ICTRP Trial Number: U1111-1158-3672). The BMI declined significantly (− 12.6%) in the treatment arm (N = 39) during the 6-month weight loss intervention. This was associated with a significant reduction in hsCRP (− 45.84%) and circulating CD14+ cells (− 21.0%). Four genes were differentially expressed (DEG’s) in CD14+ cells following weight loss (ZRANB1, RNF25, RB1CC1 and KMT2C). Comparative analyses of paired CD14+ monocytes and subcutaneous adipose tissue samples before and after weight loss did not identify common genes differentially regulated in both sample types. Lifestyle-induced weight loss is associated with specific changes in gene expression in circulating CD14+ monocytes, which may affect ubiquitination, histone methylation and autophagy.

High-Dose, Diazoxide-Mediated Insulin Suppression Boosts Weight Loss Induced by Lifestyle Intervention.

Obesity-related hyperinsulinism may impede lifestyle-initiated weight loss. Proof-of-concept study to investigate the amplifying effects of diazoxide (DZX)-mediated insulin suppression on lifestyle-induced weight loss in nondiabetic, hyperinsulinemic, obese men. Twelve-month study comprising an initial 6-month, double-blind trial, followed by a partially de-blinded 6-month extension in men with obesity with a body mass index of 30 to 37.5 kg/m2 and a fasting serum C-peptide level >1.00 nM. Patients were randomized into three treatment groups: DZX + placebo (DZX + PL), DZX + metformin (DZX + MTF), and double PL (PL + PL). At 6 months, DZX treatment was associated with a 6.1-kg PL-subtracted decline in fat mass (FM), and at 12 months, FM had decreased by a total of 15.7 ± 2.5 kg. Twelve months of DZX treatment was also associated with a significant decline in systolic (-6.6%) and diastolic (-8.6%) blood pressure and low-density lipoprotein-cholesterol (-18%) and triglycerides (-43%) and a 39% rise in high-density lipoprotein-cholesterol. These effects were achieved at the cost of a small rise in fasting glucose (95% CI: 0.2 to 1.0 mM) and hemoglobin A1c (95% CI: -0.08% to 0.44%). There were no differences between DZX monotherapy and the combination of DZX + MTF. High-dose DZX treatment of 1 year resulted in a substantial decrease in FM, blood pressure, and lipid levels at the cost of a small rise in blood glucose levels.

Early Effects of Sleeve Gastrectomy (SG) on Systemic and Organ-Specific Dietary Fatty Acid Uptake, Postprandial Free Fatty Acids (FFA), and Glucose Metabolism in Type 2 Diabetes (T2D)

Postprandial dietary fatty acid (FA) biodistribution is impaired in subjects with glucose intolerance, with decreased FA storage in adipose tissues (AT) and increased FA uptake by the myocardium. These abnormalities are improved after 1 year of lifestyle-induced weight loss. Bariatric surgery leads to early metabolic improvements before weight loss, but the early effects on dietary FA metabolism and biodistribution have never been studied. 9 subjects with T2D underwent a 6-hour postprandial metabolic protocol before and 12 days after SG. A liquid meal containing [U-13C]-palmitate and [2H]-glucose was ingested at time 0, with an IV perfusion of [3H]-glucose and [7,7,8,8-2H]-palmitate, allowing quantification of glucose absorption, endogenous glucose production (EGP), lipolysis and dietary FA spillover. A capsule containing a positron-emitting long-chain FA analog (18FTHA) was taken with the meal for the quantification of organ-specific dietary FA uptake using PET/CT (n=6). Twelve days after SG, whole body and hepatic insulin sensitivity increased significantly whereas fasting and postprandial EGP decreased. Postprandial GLP-1, GIP, PYY and glucagon were higher after vs. before SG. Postprandial AUC of FFA (175 vs. 228 mmol/Lx min; p&amp;lt; 0.05) and total FA oxidation were higher (p&amp;lt; 0.02 from 180 min to 360 min), but dietary FA oxidation was reduced after SG (p&amp;lt; 0.002 from 180 min to 360 min). After SG, uptake of dietary FA 6 hours after the meal was reduced in the myocardium (mean SUV 2.07± 0.66 vs. 1.36± 0.44; p=0.06) and was increased in visceral AT (mean SUV 0.24± 0.2 vs. 0.42± 0.2; p=0.03), without changes in other organs. In conclusion, there is reduced myocardial and increased visceral AT uptake of dietary FA associated with reduced dietary FA oxidation and increased FFA mobilization and oxidation, concomitant with reduced EGP and insulin sensitization in patients with T2D early after SG. Disclosure A. Carreau: None. C. Noll: None. B. Guerin: None. L. Biertho: Advisory Panel; Self; Novo Nordisk Inc.. Consultant; Self; Johnson &amp; Johnson Services, Inc., Valeant Pharmaceuticals International, Inc.. E.E. Turcotte: None. A. Tchernof: Research Support; Self; Johnson &amp; Johnson Services, Inc., Medtronic. A. Carpentier: Consultant; Self; UniQure, Janssen Pharmaceuticals, Inc., Siemens. Research Support; Self; Caprion, Merck Sharp &amp; Dohme Corp., GlaxoSmithKline plc., Novartis Pharmaceuticals Corporation, AstraZeneca, Bristol-Myers Squibb Company, Sanofi-Aventis, Pfizer Inc., Novo Nordisk Inc., Exelixis, Amgen Inc..

Impact of weight loss achieved through a multidisciplinary intervention on appetite in patients with severe obesity.

The impact of lifestyle-induced weight loss (WL) on appetite in patients with obesity remains controversial. This study aimed to assess the short- and long-term impact of WL achieved by diet and exercise on appetite in patients with obesity. Thirty-five (22 females) adults with severe obesity (body mass index: 42.5 ± 5.0 kg/m2) underwent a 2-yr WL program focusing on diet and exercise. Body weight (BW), cardiovascular fitness (V̇o2max), appetite feelings, and plasma concentrations of insulin, active ghrelin (AG), glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and cholecystokinin (CCK), in the fasting and postprandial states, were measured at baseline (B), week 4 (W4), and 1 and 2 yr (and average values for all fasting and postprandial time points computed). BW was significantly reduced and V̇o2max (ml·kg-1·min-1) increased at all time points compared with B (3.5, 8.1, and 8.4% WL and 7, 11, and 8% increase at W4 and 1 and 2 yr, respectively). Basal hunger and average hunger and desire to eat were significantly increased at 1 and 2 yr. Basal fullness was significantly increased at W4, and average ratings were reduced at 1 yr. Average AG and PYY were significantly increased, and insulin was reduced, at all time points compared with B. Average GLP-1 was reduced at W4, and CCK was increased at 2 yr. After lifestyle-induced WL, patients with severe obesity will, therefore, have to deal with increased hunger in the long term. In conclusion, sustained WL at 2 yr achieved with diet and exercise is associated with increased hunger feelings and ghrelin concentration but also increased postprandial concentrations of satiety hormones.

Comparison among criteria to define successful weight-loss maintainers and regainers in the Action for Health in Diabetes (Look AHEAD) and Diabetes Prevention Program trials

Background: Given the low rates of successful weight maintenance after lifestyle-induced weight loss, it is critical to develop approaches that distinguish successful weight-loss maintainers from regainers.Objective: The aim of this study was to compare published categorization criteria that differentiate maintainers and regainers via quantitative agreement.Design: The study used publicly available data from Look AHEAD (Action for Health in Diabetes; n = 1791) and Diabetes Prevention Program (DPP; n = 613) participants with ≥3% initial weight loss after lifestyle interventions and 4-y follow-up data. Eight previously published criteria defining maintainers and regainers were compared with respect to number of participants and concordance via agreement statistics. Criteria were assessed separately among those with 3-9% and ≥10% initial weight loss.Results: Regainers had higher body weight at year 4 than did maintainers (mean difference range: 6.6-11.9 kg in Look AHEAD; 11.5-14.6 kg in DPP; P < 0.0001). Assessing concordance among criteria, agreement was dependent on initial weight loss. Among those with 3-9% initial weight loss in both cohorts, 9 of 28 comparisons were concordant (agreement ≥80%). Among those with ≥10% initial weight loss, 7 of 28 comparisons in Look AHEAD and 13 of 28 in the DPP were in high agreement. The definition of successful weight-loss maintenance "regaining ≤25% of initial weight loss during maintenance" showed high agreement with the most commonly used definition of "staying ≥10% below initial weight" among those with ≥10% initial weight loss (agreement: 85.0% in Look AHEAD; 87.4% in DPP). The same definition of ≤25% regain showed high agreement with the definition of staying ≥5% below initial weight among those with 3-9% initial weight loss (agreement: 91.6% in Look AHEAD; 90.5% in DPP).Conclusions: Although all of the criteria discriminated on the basis of weight loss, many showed low agreement, which limited cross-study comparisons. Among criteria with high agreement, the definition of successful weight maintenance "regaining ≤25% of initial weight loss during maintenance" is a preferred definition of success, given the realistic challenges of maintaining 100% weight loss and flexible application in populations with high initial weight-loss variations. This trial was registered at clinicaltrials.gov as NCT00017953 (Look AHEAD) and NCT00004992 (DPP).

Abstract MP003: Development and Validation of a Prediction Model of Weight Loss Maintenance or Regain at 4 Years in the Look AHEAD Trial

Introduction: The development of type 2 diabetes is strongly associated with excess weight gain and can often be partially ameliorated or reversed by weight loss. While many lifestyle interventions have resulted in successful weight loss, strategies to maintain the weight loss have been considerably less successful. Prior studies have identified multiple predictors of weight regain, but none have synthesized them into one analytic stream. Methods: We developed a prediction model of 4-year weight regain after a one-year lifestyle-induced weight loss intervention followed by a 3 year maintenance intervention in 1791 overweight or obese adults with type 2 diabetes from the Action for Health in Diabetes (Look AHEAD) trial who lost ≥3% of initial weight by the end of year 1. Weight regain was defined as regaining &lt;50% of the weight lost during the intervention by year 4. Using machine learning we integrated factors from several domains, including demographics, psychosocial metrics, health status and behaviors (e.g. physical activity, self-monitoring, medication use and intervention adherence). We used classification trees and stochastic gradient boosting with 10-fold cross validation to develop and internally validate the prediction model. Results: At the end of four years, 928 individuals maintained ≥50% of their initial weight lost (maintainers), whereas 863 did not met that criterion (regainers). We identified an interaction between age and several variables in the model, as well as percent initial weight loss. Several factors were significant predictors of weight regain based on variable importance plots, regardless of age or initial weight loss, such as insurance status, physical function score, baseline BMI, meal replacement use and minutes of exercise recorded during year 1. We also identified several factors that were significant predictors depending on age group (45-55y/ 56-65y/66-76y) and initial weight loss (lost 3-9% vs. ≥10% of initial weight). When the variables identified from machine learning were added to a logistic regression model stratified by age and initial weight loss groups, the models showed good prediction (3-9% initial weight loss, ages 45-55y (n=293): ROC AUC=0.78; ≥10% initial weight loss, ages 45-55y (n=242): ROC AUC=0.78; (3-9% initial weight loss, ages 56-65y (n=484): ROC AUC=0.70; ≥10% initial weight loss, ages 56-65y (n=455): ROC AUC = 0.74; 3-9% initial weight loss, ages 66-76y (n=150): ROC AUC=0.84; ≥10% initial weight loss, ages 66-76y (n=167): ROC AUC=0.86). Conclusion: The combination of machine learning methodology and logistic regression generates a prediction model that can consider numerous factors simultaneously, can be used to predict weight regain in other populations and can assist in the development of better strategies to prevent post-loss regain.

Serum bile acids and GLP-1 decrease following telemetric induced weight loss: results of a randomized controlled trial.

Bile acids (BAs) are increasingly recognised as metabolic regulators, potentially improving insulin sensitivity following bariatric surgery. However, physiological relevance of such observations remains unknown. Hence, we analysed serum BA composition and associated gut-derived hormone levels following lifestyle-induced weight loss in individuals with metabolic syndrome (MetS). 74 non-smoking men (45–55 yr) with MetS were randomised to a lifestyle-induced weight loss program (supervision via telemonitoring) or to a control arm. Before and after a 6 months intervention period clinical and laboratory parameters, body composition, serum BA profile, FGF-19, and GLP-1 concentrations were determined in fasting blood samples. 30 participants in the control and 33 participants in the treatment arm completed the study and were included in the data analysis. In participants of the treatment arm lifestyle-induced weight loss resulted in markedly improved insulin sensitivity. Serum levels of BA species and total GLP-1 decreased, while FGF-19 remained stable. Serum BA composition changed towards an increased 12α-hydroxylated/non-12α-hydroxylated ratio. None of these parameters changed in participants of the control arm. Our results demonstrate that improved metabolic control by lifestyle modifications lowers serum levels of BAs and GLP-1 and changes serum BA composition towards an increased 12α/non-12α ratio (ICTRP Trial Number: U1111-1158-3672).

Is setting a criterion for ‘clinically significant weight loss’ necessary?

The prevention and treatment of obesity remain major public health challenges. Obesity management guidelines worldwide have identified weight loss as the primary target to determine treatment success as weight loss is associated with benefit across a wide range of health outcomes (1). How much weight loss is required for health benefit, however, continues to be the source of uncertainly and debate. In recent years, it has been suggested that “clinically significant weight loss” should be set at a threshold of 5% (2). Although it is true that for most health outcomes a 5% weight loss is associated with benefit, it is also true that for adults who adopt and sustain physical activity combined with a healthful diet, significant health benefits are achieved in association with very modest (less than 3%) or even no weight loss (3). Strong evidence in support of this notion comes from the Diabetes Prevention Study wherein participants who increased physical activity for about 150 min per week but did not achieve “clinically significant weight loss,” reduced diabetes incidence by 44% (4), observations consistent with the findings of the Diabetes Prevention Program (5). The findings from these and numerous randomized controlled trials (3) consistently report that physical activity is associated with benefit for many health outcomes with or without weight loss. In the present issue of Obesity, Swift et al. (6) report the findings of an ancillary study designed to determine the effects of exercise amount on body weight and selected cardiometabolic risk factors. A total of 330 women performed 6 months of aerobic exercise at 4 kcal per kilogram per week (4KKW), 8KKW, or 12 KKW (50%, 100%, and 150% of recommended levels, respectively). The authors distinguished the participants by the weight loss they achieved; those who lost between 3% and 4.9% were classified as having modest weight loss (MWL), whereas those who lost at least 5% were identified as having achieved clinically significant weight loss (CWL). The findings of this rigorously controlled study suggest that exercise performed for about 150 min or less per week may not be sufficient to achieve a 5% weight loss for many adults over a relatively short duration. Given the rather low levels of exercise-induced energy expenditure in this trial, the findings are not surprising and confirm the positive dose-response relationship between exercise and weight loss (7). In fact, 300 min of weekly exercise is recommended if weight loss in the order of 5% to 10% is desired (8). An extremely important observation in this study was that the statistically significant reductions in insulin resistance observed within the MWL group was not different from the CWL group, thus confirming that improvements in insulin action are achievable in association with very modest exercise-induced weight loss. That the authors did not observe significant reductions in other risk factors regardless of weight loss is likely explained by the remarkably normal cardiometabolic risk profile prior to intervention. It is suggested that the 5% clinically significant weight loss threshold for effective obesity management is “here to stay” (2). While the veracity of this contention will continue to be the source of debate among academics, its interpretation for many practitioners and obese adults may well be that, for effective obesity management, substantial weight loss is required for benefit. This would be an unfortunate interpretation and one that may lead obese adults who are unable to make the major changes in behavior required to sustain a 5% weight loss in today's environment to become frustrated and consequently discontinue physical activity and/or the consumption of a healthy diet. Given that the health benefits of lifestyle-induced weight loss typically occur in a dose-response manner (1, 3-5), the need to establish “clinically significant” weight loss targets, a strategy with little evidence of success, seems unnecessary. A revised approach would be to target the causal behaviors—physical activity combined with a healthful diet. Given the plethora of health benefits associated with increasing physical activity regardless of weight loss, and that sustained weight loss is unlikely to occur without increasing physical activity (8), changing the focus for effective obesity management from the bathroom scale to the adoption of healthy behaviors is an idea worth considering.

Major Increase in Microbiota-Dependent Proatherogenic Metabolite TMAO One Year After Bariatric Surgery.

Background: Trimethylamine-N-oxide (TMAO) is formed in the liver from trimethylamine (TMA), a product exclusively generated by the gut microbiota from dietary phosphatidylcholine and carnitine. An alternative pathway of TMAO formation from carnitine is via the microbiota-dependent intermediate γ-butyrobetaine (γBB). Elevated TMAO levels are associated with cardiovascular disease (CVD), but little is known about TMAO in obesity. Given the proposed contribution of microbiota alterations in obesity and type 2 diabetes (T2D), we investigated the potential impact of obesity, lifestyle-induced weight loss, and bariatric surgery on plasma levels of TMAO, its microbiota-dependent intermediate γBB, and its diet-dependent precursors carnitine and choline.Methods: TMAO, γBB, carnitine, and choline were measured by high-performance liquid chromatography in 34 obese individuals (17 with and 17 without T2D) undergoing bariatric surgery and 17 controls.Results: TMAO was not elevated in obese patients or reduced by lifestyle interventions but increased approximately twofold after bariatric surgery. Similar to TMAO, plasma levels of γBB were not influenced by lifestyle interventions but increased moderately after bariatric surgery. In contrast, carnitine and choline, which are abundant in nutrients, such as in red meat and eggs, and not microbiota dependent, were reduced after lifestyle interventions and rebounded after bariatric surgery.Conclusions: The major increase in TMAO after bariatric surgery was unexpected because high TMAO levels have been linked to CVD, whereas bariatric surgery is known to reduce CVD risk. Prospective studies of gut microbiota composition and related metabolites in relation to long-term cardiovascular risk after bariatric surgery are warranted.