The Physiology Of the WEight Reduced State (POWERS) study is a multi-center NIH-funded clinical trial designed to determine the physiological basis for variability in weight loss maintenance among adults with obesity following participation in a behavioral weight loss program. Two hundred and five healthy adults, aged 25-<60 years, with body mass index 30-<40 kg/m2 complete up to four serial assessments (before weight loss; after ≥7% weight loss; and four and 12 months later). This report, one in a five-part series on the POWERS study design, provides the rationale for and description of behavioral measures. Standardized laboratory meals are used to measure energy intake and eating-related behaviors. Behavioral and neurocognitive factors related to eating (e.g., food-choice decision making, taste preferences, reward, self-control) are assessed via computer-based tasks and self-report questionnaires. Functional and structural neuroimaging augment the behavioral assessments by identifying underlying neural circuitry. Psychological factors related to weight regulation (e.g., self-monitoring, stigma, self-efficacy) are assessed via self-report questionnaires. Free-living physical activity and sleep are measured via accelerometry, polysomnography and self-report questionnaires. We will evaluate how changes, integrated values and patterns in these predictors and components of energy intake and energy expenditure contribute to individual variability in weight change during the 12 months following weight loss. We anticipate that extensive phenotyping using sophisticated eating behavior paradigms and assessments of critical components of energy expenditure before and after weight loss will lead to improved predictions of successful weight loss maintenance. This, in turn, will inform more effective treatments for long-term sustained weight loss.
Background: In Australia, the rising prevalence of metabolic syndrome (MetS) presents a significant public health challenge. However, research on geographic and ethnic disparities remains limited. This study aimed to investigate the prevalence and temporal trends of MetS by geographic remoteness and between Indigenous and non-Indigenous Australians.
Methods: We analysed data from 44,760 adults (aged ≥18 years) derived from the National Health Survey (2014-2015 and 2017-2018) and the National Aboriginal and Torres Strait Islander Health Survey (2012-2013 and 2018-2019). Weighted prevalence estimates of MetS were calculated overall and stratified by remoteness. The Average Annual Rate of Change (AARC) in MetS prevalence was computed to assess temporal trends.
Results: MetS prevalence varied notably by remoteness and ethnicity. In the most recent surveys, 7.1% (95% CI: 6.19-8.19) of Indigenous adults (2018-2019) and 4.6% (95% CI: 4.23-4.99) of non-Indigenous adults (2017-2018) had MetS. Prevalence was higher in remote areas for both groups. Among non-Indigenous adults, MetS declined across most regions but increased in remote areas from 4.5% to 7.1% (AARC: +15.77%), while among Indigenous adults it remained stable in remote areas but rose in major cities and regional settings. Central obesity and type 2 diabetes (T2D) were the most prominent contributors to MetS among Indigenous adults, whereas hypertension and high cholesterol were more prevalent among non-Indigenous adults in regional areas. Central obesity was the most common MetS risk factor, affecting 57.4% (95% CI: 55.14-59.63) of Indigenous and 40.9% (95% CI: 39.90-41.85) of non-Indigenous adults. High cholesterol was the least common risk factor among Indigenous adults (7.6% [95% CI: 6.58-8.67]), whereas elevated blood sugar was the least common among non-Indigenous adults (4.8% [95% CI: 4.44-5.21]).
Conclusions: Substantial disparities in MetS exist across Australia, disproportionately affecting Indigenous Australians and residents of remote areas. Culturally tailored, region-specific interventions targeting obesity are urgently needed through Local Health Districts and Aboriginal Community Controlled Health Organisations.
Objective: To evaluate the efficacy of a comprehensive cognitive intervention as an add-on to a standard behavioral weight-loss intervention (BWLI) in improving anthropometric measures in individuals with excess weight.
Participants: This randomized controlled trial included 148 participants (126 women; mean BMI = 31.62 kg/m²); 86.5% participants (n = 128) completed the study.
Methods: Participants were randomized into three groups: (1) Cognitive group (received four cognitive trainings: inhibitory control, approach-avoidance bias modification, implementation intentions, and episodic future thinking); (2) Sham group (received placebo cognitive interventions); and (3) Control group (no cognitive intervention). All three groups received BWLI. Cognitive trainings were delivered through four consecutive 90-min online group sessions. BMI, weight, percentage of weight loss (%WL), and waist-to-height ratio (WHtR) were assessed at baseline, post-treatment, and 3- and 6-month follow-ups. Mixed 3 (group) × 3 (time point) analysis were conducted to examine changes over time and between groups. Chi-squared test was used to explore group differences in reaching a clinically meaningful %WL.
Results: Significant group-by-time effects interactions were found for BMI (p = 0.009), weight (p = 0.003), %WL (p = 0.004) and WHtR (p = 0.041). Post hoc analyses showed greater reductions in all anthropometric measures in the Cognitive group compared to the Control group at post-intervention and at both follow-ups. Further, only the Cognitive group showed significant improvements over time. At 6-month follow-up, effect sizes were moderate in the Cognitive group, small in the Sham group, and negligible to small in the Control group. A higher proportion of participants in the Cognitive group achieved a clinically meaningful %WL.
Conclusions: A comprehensive cognitive training delivered as an add-on to BWLI improved anthropometric outcomes in individuals with excess weight, with sustained effects over 6 months.
Background: Adipose lipolysis, a process involving the degradation of triglycerides and the release of fatty acids and glycerol, is an important biological event in lipid metabolism. Canagliflozin (Cana), an oral antidiabetic drug, regulates blood glucose by inhibiting sodium-glucose cotransporter 2 (SGLT2) in renal tubules and has also been shown to improve lipid metabolism in adipocytes. This study aims to determine whether Cana directly affects adipose lipolysis and to explore the underlying mechanistic pathways.
Method: Primary mature adipocytes and differentiated preadipocytes isolated from the epididymal fat pads of Sprague-Dawley rats were used as in vitro models. The effects of Cana on glycerol release and lipase activity were evaluated using ELISA and Western blot analyses.
Results: Cana treatment directly inhibited basal glycerol release and lipase activity in both primary adipocytes and topically administered adipose tissue, achieving a dose-dependent 35% to 65% suppression of lipolysis. This was associated with a 2.3-fold decrease in the level of HSL phosphorylated at the Ser660 site. Using differentiated adipocytes derived from the human Simpson-Golabi-Behmel syndrome (SGBS) pre-adipocyte cell line, we found that Cana significantly attenuated glycerol release (~32% to 53% reductions) induced by lipolysis. Moreover, Cana exerted antilipolytic effects in models of both acute (isoprenaline-induced) and chronic (tumor necrosis factor-α-induced) lipolysis. Mechanistically, the antilipolytic effect of Cana was mediated through activation of the PI3K/AKT pathway and reduction of cAMP production.
Conclusion: In conclusion, Cana regulates adipocyte lipolysis via an SGLT2-independent signaling pathway, which enhances our understanding of its role in modulating lipid metabolism.
Background: The combined and interactive effects of multiple lifestyle behaviours on obesity risk are not well understood. We used Multilevel Analysis of Individual Heterogeneity and Discriminatory Accuracy (MAIHDA) to examine how adherence to public health recommendations for five lifestyle behaviours affects BMI and obesity risk.
Methods: The sample included 139,540 men and 125,455 women from the UK Biobank. We categorized fruit and vegetable intake, physical activity, sleep duration and alcohol intake as binary variables (meeting vs. not meeting guidelines), and smoking status into three categories (previous, current, never). These categories were combined to form 48 unique strata, representing all possible combinations of the five behaviours. Linear and binary logistic MAIHDA models were used, with individuals nested within strata, and BMI and obesity status (obesity vs. normal weight) as outcomes. Three models were employed: Model 1 (null), Model 2 (with fixed effects for lifestyle behaviours), and Model 3 (with confounders and fixed effects). Variance Partition Coefficient (VPC), Proportional Change in Variance (PCV), and predicted BMI and obesity risk were estimated.
Results: For both sexes, strata with the lowest obesity risk were associated with meeting most recommendations, while strata with the highest risk were linked to meeting few. Logistic Model 1 VPCs revealed 7% of variance in obesity risk among males and 5% among females was explained by between-strata differences. In Model 3, VPCs attenuated to 0.5% among males and 0.1% among females, suggesting differences in obesity risk were largely additive effects. PCVs from Model 3 also indicated primarily additive rather than interactive effects. Results were similar for BMI in the linear models.
Conclusions: Using a novel statistical approach, this study shows that additive effects of multiple lifestyle behaviours predominantly explain differences in BMI and obesity risk. Meeting more public health lifestyle recommendations is important in mitigating obesity risk.
Background: Few studies have compared gut hormone responses between bariatric procedures. This study compared Roux-en-Y and one-anastomosis gastric bypass (RYGB and OAGB) regarding glucagon-like peptide-1 (GLP-1), secretin, and glucose-insulin dynamics.
Methods: This study included 41 participants (RYGB: n = 21, OAGB: n = 20) from the randomized RYSA trial with similar amounts of bypassed intestine between the procedures. Plasma GLP-1, secretin, glucose, insulin, and C-peptide were measured during a 360-min mixed-meal test before, and at 6- and 12-months after surgery. Outcomes included total and early-phase (0-60 min) areas under the curve (AUCs) and peak concentrations. Visual analogue scales were used to measure hunger and satiety.
Results: Both procedures resulted in ~25% weight loss and marked metabolic improvements over 12 months. While fasting GLP-1 remained largely unchanged, postprandial concentrations rose markedly at 6 months (total AUC increase in RYGB: ~330%, OAGB: ~259%; p < 0.001) and remained elevated at 12 months. The increases in early-phase GLP-1 AUC were 31% higher in RYGB than OAGB at 6 months (95% CI: 3 to 68; p = 0.030) and 25% higher at 12 months (95% CI: -2 to 59; p = 0.072). Peak GLP-1 increases were significantly higher ( ~ 32%) after RYGB at both follow-ups (p < 0.05). Postprandial reduction in hunger was greater after RYGB than OAGB from baseline to 12 months. Fasting or postprandial secretin concentrations showed no significant changes. Both operations were associated with decreased fasting glucose, insulin, and C-peptide; increased early glucose but decreased glucose total AUCs; and increased insulin early AUC and C-peptide total and early AUCs. Glucose early-phase AUC and peak concentration increases were greater after RYGB than OAGB.
Conclusions: Both RYGB and OAGB lead to markedly enhanced postprandial GLP-1 responses, with no corresponding change in secretin levels. RYGB produces higher early postprandial increases in GLP-1 and glucose than OAGB, demonstrating that procedural differences can influence gut hormone and glucose responses.
Introduction: The expression and/or activity of sirtuins (SIRTs), nicotinamide adenine dinucleotide (NAD+)-dependent enzymes that regulate cellular energy metabolism, is decreased in obesity and in aging in animal models. However, the impact of obesity compared to aging on NAD+/SIRT expression in human white adipose tissue (AT) remains unexplored. Here, we unravel the effects of obesity and aging on the expression of NAD+/SIRT pathway and their associated genes in subcutaneous AT of identical twin pairs discordant for weight, in two age groups.
Methods: We examined 49 monozygotic twin pairs discordant for BMI (within-pair difference in BMI ≥ 2.5 kg/m2, with mean BMIs 25.6 kg/m2 (leaner) and 30.8 kg/m2 (heavier), aged 22-38 and 56-69 years. Detailed phenotyping included body composition, insulin resistance (oral glucose tolerance test) and plasma lipids and inflammation markers. RNA sequencing and DNA methylation analyses in AT identified differentially expressed and methylated NAD+/SIRT pathway genes in obesity and aging, with linear mixed models linking gene expression to metabolic features.
Results: SIRT5 and NAD+ biosynthetic genes were downregulated in AT in both obesity and aging. Obesity was characterized by downregulation of AT NAD+/SIRT genes, and NAD+/SIRT regulated mitochondrial oxidative metabolism genes, and upregulation of stress markers. Aging showed a downregulation of AT PARPs, except upregulation for PARP1, a main consumer of NAD+. Mitochondrial metabolism and glycolysis genes were linked to corresponding DNA methylation. Downregulation of NAD+/SIRT genes correlated with increased adiposity, insulin resistance, inflammation, and dyslipidemia.
Conclusion: Impaired NAD+/SIRT metabolism in AT may play a key role in obesity- and aging-related diseases. Both conditions are characterized by downregulation of NAD+/SIRT pathway genes, correlating with increased adiposity, insulin resistance, inflammation, and dyslipidemia. Obesity uniquely disrupts expression of NAD+/SIRT regulated mitochondrial genes, while aging is characterized by altered PARP expression, particularly increased PARP1, likely exacerbating metabolic dysfunction in AT.
Obesity is a chronic, debilitating condition with complex biological, psychosocial, and behavioral underpinnings. While the cardiometabolic consequences are reasonably well-established, the often-forgotten bidirectional association between obesity and mental health disorders, including anxiety, eating disorders, depression, and even suicidal ideations, is rarely assessed as a primary endpoint in obesity intervention studies. Similarly, documents summarizing and comparing various types of obesity interventions and their effects of mental health in this rapidly evolving field are scarce. This narrative review synthesizes the evidence on the psychological impact of lifestyle, pharmacological, and surgical interventions in the treatment of obesity. Special focus is placed on glucagon-like peptide-1 (GLP-1) receptor agonists, given their rising global use and emerging concerns regarding mental health safety. A thorough literature review was conducted across the MEDLINE, Embase, and Cochrane databases, focusing on meta-analyses, systematic reviews, and clinical trials published up to June 2025. Studies examining psychological outcomes in patients undergoing lifestyle modifications, pharmacotherapy, or bariatric surgery for weight loss were included. Mental health domains considered included quality of life, anxiety, depression, and suicidality. Due to the vast array of obesity interventions and the broad nature of mental health in the literature, this review was conducted to provide a narrative summary. Behavioral interventions consistently showed no harm to mental health and demonstrated modest improvements in depression and mental health-related quality of life. Bariatric surgery was associated with short-to-medium-term reductions in depressive and anxiety symptoms, though long-term benefits were attenuated, with some studies reporting increased suicidality after five years. Pharmacotherapies, including orlistat, bupropion/naltrexone, and phentermine/topiramate, showed mixed psychiatric impacts. The GLP-1 receptor agonists (Semaglutide, liraglutide, Tirzepatide) have shown an improvement in patient-reported mental wellbeing in several trials. Concerningly, pharmacovigilance data initially suggested a possible link with suicidality; however, subsequent robust cohort studies and meta-analyses have refuted this association. Mental health is a critical yet underprioritized element of obesity management. The current evidence suggests that most weight loss interventions are psychologically safe or beneficial, but long-term data remain limited, particularly for GLP-1 receptor agonists. Future randomized trials must incorporate mental health as a prespecified outcome, and individualized treatment approaches should integrate psychological support to optimize long-term outcomes. This review has summarized, side-by-side, the various outcomes of obesity interventions on mental health.
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