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.
Background: Movement behaviours, including moderate-to-vigorous-intensity physical activity (MVPA), light-intensity physical activity (LPA), sedentary behaviour (SB), and sleep, influence childhood adiposity. However, their collective impact on adiposity from a sex-specific perspective remains underexplored. Our research examined the sex-specific longitudinal associations of 24-h movement behaviours with body mass index (BMI) and abdominal adiposity among children.
Methods: In the Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort study, we repeatedly measured 24-h movement behaviours using wrist-worn accelerometers (ActiGraph GT3x) and assessed adiposity (BMI, abdominal circumference, and MRI-based abdominal fat volumes) at three time points (ages 5.5-6, 7.5-8, and 10-10.5 years) within the same children in a longitudinal design. Compositional multivariable linear mixed-effect modelling and isotemporal substitution were used to estimate the associations.
Results: 531 children (49.5% girls) were included in the analysis. Significant interactions between movement behaviours and sex were observed across all outcomes. In girls, higher MVPA relative to other behaviours was linked to lower BMI [-0.8 (-1.5, -0.1) kg/m²] and total abdominal adiposity [-225.5 (-451.6, -2.5) mL], while in boys, longer sleep duration was associated with lower BMI [-1.6 (-3.2, -0.1) kg/m²] and total abdominal adiposity [-624.2 (-1225.6, -31.3) mL]. The isotemporal substitution model showed that replacing 30 min of LPA/SB with MVPA reduced BMI and abdominal circumference by 1-2% and MRI-measured abdominal adiposity by 6-9% in both sexes. However, replacing LPA/SB with sleep reduced BMI and abdominal circumference by 1% and MRI-measured adiposity by 3-6% only in boys, with no changes in girls. These associations were pronounced on visceral adiposity.
Conclusion: This study highlights sex-specific associations of movement behaviours with adiposity in school-aged children, with stronger associations observed in MRI-derived measures compared to conventional adiposity indices. Replacing LPA/SB with MVPA reduced BMI and abdominal adiposity in both sexes, with particularly pronounced effects on visceral adiposity. However, sleep replacement benefits were observed only in boys, suggesting the need for gender-sensitive approaches in lifestyle interventions.
Objective: Bariatric surgery is the most effective long-term treatment for obesity, but how different surgical techniques affect metabolic outcomes remains unclear. Bile acids (BAs), increasingly recognized as metabolic regulators, rise postprandially after surgery and may mediate some of these effects. This exploratory study investigates the differential impact of Roux-en-Y gastric bypass (RYGB) and one-anastomosis gastric bypass (OAGB) on BA profiles and associated metabolic outcomes over one year.
Methods: Forty-five patients with obesity (15 men, 30 women; mean (SD) age 46.6 (7.1) years) were randomized to receive either RYGB (n = 24) or OAGB (n = 20). Clinical assessments, body composition measurements (Dual energy X-ray absorptiometer), fasting blood tests including lipids and inflammation markers, 360-minute mixed meal test, and oral glucose tolerance test were conducted 4-6 weeks before and at 6 and 12 months after operation. Plasma total and 15 individual BAs (LC-MS) were measured at eight time points during the mixed meal test.
Results: RYGB led to an increase in postprandial secondary BAs from baseline to 12 months (p = 0.004), particularly deoxycholic acid (DCA; p < 0.001) and glycodeoxycholic acid (GDCA; p = 0.006) compared with OAGB. In contrast, OAGB led to an increase in postprandial primary taurine-conjugated BAs (p = 0.039), especially taurochenodeoxycholic acid (TCDCA; p = 0.036) compared with RYGB. Similarly, RYGB increased unconjugated secondary BAs, especially DCA, whereas OAGB increased conjugated primary BAs, like TCA and GCA during fasting. Metabolic improvements were similar in both groups. Post-RYGB increases in secondary BAs correlated with improved insulin sensitivity and post-OAGB increases in primary taurine-conjugated BAs correlated with higher fat mass preservation during weight loss.
Conclusions: RYGB and OAGB differentially modulate BA profiles over one year, with RYGB increasing secondary BAs and OAGB increasing taurine-conjugated primary BAs. These findings suggest distinct mechanisms contributing to their metabolic benefits.
Background: People exist at a combination of different individual and neighbourhood deprivations. Each of these combinations may have a unique impact on health. However, little is known about the intersectional inequality of these combinations on general and central obesity, including when considering their demographics. This study aims to answer these questions.
Methods: The sample comprised 452,339 participants from the UK Biobank study. Individuals were grouped into 320 intersectional strata according to their household income, neighbourhood deprivation, sex, ethnicity and age. Linear and logistic multilevel analysis of individual heterogeneity and discriminatory accuracy was used to establish the total, additive and interactive inequality of body mass index (BMI), fat mass index (FMI), and waist to height ratio (WHtR), as well as the associated obesity classifications.
Results: 6.5%, 25.2% and 9.1% of the total variation in BMI, FMI and WHtR, respectively, was due to inequality between the strata. Of this, 26.5%, 3.5% and 22.0% is interactive. 79, 58 and 93 strata for BMI, FMI and WHtR demonstrate a significant interactive effect. We found some patterns; for example, affluent white women have an advantaged interactive effect, whilst deprived black women have a disadvantaged effect. Meanwhile men experience the inverse relationship. The relationship between individual and neighbourhood deprivation is not universally experienced by all strata. For example, black men living in areas of high deprivation have higher BMIs as their household income increases.
Conclusions: A large proportion of variation in general and central obesity is due to intersectional inequality, with up to 26.5% being interactive. It is important that these intersectional effects are considered when designing policy interventions to avoid policy failure, such as by focussing on groups with high total and interactive risk.
Background: Despite being a defining feature of metabolic syndrome (MetS), clinical assessment of IR remains challenging, due to the costs of reference methods and the numerosity of IR indices. Furthermore, to which extent IR contributes to MetS, while controlling for altered body composition, is still largely unexplored.
Objectives: The present work aims at proposing new cut points for IR among people with overweight and obesity, assessing the concordance of different IR definitions and investigating how IR interacts with body composition in predicting MetS status.
Subjects: 665 patients were assessed for potential enrolment, using a cross-sectional design. The following inclusion criteria were applied: age ≥18 years, body mass index ≥25 kg/m2, White European, no fulfilled criterion for diabetes mellitus, no current pregnancy.
Methods: Concordance of previously validated IR definitions was assessed by Cohen's κ. ROC curve analysis with 5-fold cross-validation was used to determine novel cut points for IR indices based on MetS presence. Finally, mediation analysis was employed to test whether IR mediates the relationship between body composition indices (i.e., fat mass-to-fat-free mass ratio, FM:FFM and appendicular lean soft tissue-to-visceral fat area ratio, ALST:VFA) and MetS.
Results: A total of 515 patients were included in the final analysis (females: 80.9%; MetS prevalence: 40%). Overall, IR definitions which previously validated against the hyperinsulinemic-euglycemic clamp displayed the highest level of agreement. The following cut-points were identified from ROC curve analysis: ISI-Matsuda<3.33 (AUROC = 0.675, p < 0.001), HOMA-IR > 2.93 (AUROC = 0.663 p < 0.001), HOMA2-IR > 1.67 (AUROC = 0.651 p < 0.001). Finally, ALST:VFA but not FM:FFM significantly predicted MetS status independent of age, with the mediating role of ISI-Matsuda, HOMA-IR and HOMA2-IR.
Conclusions: IR indices mediated the effect of altered body composition (i.e., reduced appendicular muscularity and increased visceral adiposity) on MetS. Newly proposed diagnostic thresholds can aid in the identification of IR among patients at increased cardio-metabolic risk.
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