AIM:Obesity is a major contributor to insulin resistance (IR) and cardiometabolic diseases, but IR can manifest in a tissue-specific manner, resulting in discordant IR phenotypes. This study characterized metabolic and clinical differences between individuals with adipose and muscle IR. METHOD:Baseline data from 229 adults (40-75 years, BMI 25-40 kg/m2) in the PERSON study were analyzed. Participants were categorized into four groups based on indices of muscle and adipose insulin sensitivity. Muscle IR was assessed with a 7-point oral glucose tolerance test, and adipose IR was determined from fasting plasma insulin and non-esterified fatty acids. Detailed phenotyping was performed under controlled conditions and daily life. RESULTS:42% of participants displayed discordant IR patterns. Independent of muscle IR, adipose IR was associated with an adverse cardiometabolic profile, including abdominal fat accumulation, higher fasting insulin, HOMA-IR and triglycerides, greater glycemic variability, and more liver fat and hepatic IR. In contrast, individuals with isolated muscle IR maintained a relatively healthy cardiometabolic profile, though women exhibited higher muscle fat infiltration and hepatic IR. CONCLUSION:These findings demonstrate that adipose IR is more strongly and consistently linked to impaired metabolic health than muscle IR, highlighting the importance of phenotype-specific strategies for prevention and treatment.

BACKGROUND/OBJECTIVES:We investigated the effects of sweeteners and sweetness enhancers (S&SEs) in replacement of sugar on gene expression markers of adipose tissue (AT) function, adipocyte morphology, and metabolic health in adults during weight maintenance (WM) following weight loss (WL). SUBJECTS/METHODS:As part of a randomized controlled trial (European SWEET-project), 83 adults were enrolled in the study, which consists of a dietary intervention, comprising a 2-month WL-phase and a 10-month WM-phase during which participants followed a healthy diet (<10E%-added sugar) with (S&SEs group) or without S&SEs (sugar group). At baseline, after WL, and at the end of WM, we determined body composition, whole-body/tissue-specific insulin sensitivity (oral glucose tolerance test), abdominal subcutaneous adipocyte size and AT gene expression. RESULTS:WL decreased adipocyte size and improved insulin sensitivity (both P < 0.001), which was accompanied by a significant downregulation of genes involved in adipogenesis (CEBPɑ, P = 0.004), fatty acid uptake (LPL and SREBF1, both P < 0.001), fatty acid synthesis (FASN and SCD, both P < 0.001), intracellular lipolysis (ATGL, P < 0.001; HSL, P = 0.001), leptin (LEP, P < 0.001), and mitochondrial function (CS, P = 0.048) in AT. The S&SEs-group tended to regain less weight than the sugar group during the WM-phase (3.0 ± 1.2 vs. 5.9 ± 1.0 kg, respectively; P = 0.050). During the WM-phase, the S&SEs group showed a less pronounced increase in AT LPL gene expression (P = 0.041), while ABHD5 expression decreased compared to the sugar group (P = 0.036). No group differences in adipocyte size, expression of genes involved adipogenesis/oxidative metabolism/inflammation, the sweet taste receptor TAS1R3 and insulin sensitivity were found. CONCLUSIONS:S&SE-intake during a 10-month WM-phase following WL altered AT gene expression of lipolytic markers, without affecting adipocyte morphology and insulin sensitivity in adults with overweight/obesity. TRIAL REGISTRATION:ClinicalTrials.gov NCT04226911, Sweeteners and Sweetness Enhancers: Prolonged Effects on Health, Obesity and Safety (SWEET).

Liver function is impaired in metabolic dysfunction-associated fatty liver disease. Previous studies have demonstrated that oxygen availability in the tissue microenvironment affects adipose tissue and skeletal muscle function, but its hepatic effects remain unclear. This study aimed to investigate the impact of oxygen levels on metabolic pathways in HepG2 cells. Nonlipid-loaded and lipid-loaded HepG2 cells were exposed to different physiological O2 levels (5% and 10%) or standard laboratory conditions (21% O2) for 24 h. Thereafter, we determined lipid content, gene expression of metabolic markers, glycogen content, and glucose release. Furthermore, mitochondrial respiration and glycolytic activity were assessed by measuring the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR), respectively. Exposure to 5% O2 increased the expression of the gluconeogenic gene glucose-6-phosphatase catalytic subunit 1 (G6PC1) in both nonlipid-loaded and steatotic HepG2 cells compared with 21% O2 (P < 0.001). Furthermore, 5% O2 decreased the expression of lipogenic genes [sterol regulatory element binding transcription factor 1 (SREBF1), acetyl-CoA carboxylase beta (ACACB), and fatty acid synthase (FASN)] in nonlipid-loaded and/or steatotic cells (all P < 0.05), whereas genes involved in fatty acid oxidation [peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A), P < 0.001 and peroxisome proliferator-activated receptor alpha (PPARA), P = 0.038] were downregulated in steatotic cells. Low oxygen exposure increased glycogen content in nonlipid-loaded and steatotic cells (both P < 0.001) and reduced glucose release (P < 0.05). Finally, low oxygen exposure reduced OCR (P < 0.05) and increased glycolysis (P < 0.001) in both nonlipid-loaded and steatotic cells compared with 21%. In conclusion, our findings demonstrate that reduced oxygen availability in the microenvironment has marked effects on metabolic pathways in nonlipid-loaded and steatotic hepatocytes, inducing a metabolic shift to enhanced reliance on glucose as an energy source.NEW & NOTEWORTHY Oxygen availability in the tissue microenvironment affects adipose tissue and skeletal muscle function, but the effects of oxygen levels on hepatic metabolism are unclear. Low oxygen exposure altered expression of genes involved in glucose and lipid metabolism, increased glycogen content, decreased glucose release and oxygen consumption, and increased glycolytic rate compared with exposure to 21% O2 in both nonlipid-loaded and steatotic HepG2 cells, indicative of a shift to enhanced reliance on glucose as an energy source.

Abstract Background Obesity is globally recognized as a complex, multifactorial chronic disease, with biological, psychological, environmental and behavioural factors involved in both disease pathogenesis and maintenance. Although previous group-based studies demonstrated involvement of each of these factors, there is large inter-individual variability in the factors contributing to disease development as well as intervention outcomes, causing limited translatability to the individual level. This heterogeneity in treatment effectiveness might be due to differential causal and maintenance factors of obesity. To enable the transition from a one-size-fits-all approach to a more personalized approach for individuals with overweight or obesity, this study aims to investigate if and how the degree of weight loss and changes in daily life behaviour after a combined lifestyle intervention depend on individual baseline profiles comprising of person characteristics, biological, psychological, environmental and behavioural factors. Methods This study will include 600 individuals varying in BMI, 200 participants with a healthy BMI (18.5-24.9kg/m 2 ), 200 with overweight (BMI 25.0-29.9kg/m 2 ), and 200 with obesity (BMI ≥30.0kg/m 2 ). For all participants, a comprehensive individual baseline profile is created, including person characteristics, biological, psychological, environmental and behavioural factors. A clustering method is applied to identify clusters of participants with similar characteristics. Next, we examine if and how these clusters are linked to bodyweight indicators measured at baseline, and how they relate to daily lifestyle behaviour, as measured by ecological momentary assessment (EMA) using a smartphone app and sensor technology (3-week measurements). Individuals with overweight or obesity will be randomized to the intensive lifestyle intervention or a lifestyle information condition, to determine if treatment response can be predicted based on cluster characteristics, how daily lifestyle behaviour changes after an intervention, and how changes in daily lifestyle behaviour relate to treatment response. Discussion The End of Average study aims to characterize a large set of individuals varying in body weight to predict intervention effectiveness measured as changes in body weight indicators and in daily lifestyle behaviours. If reliable predictors of treatment success can be identified, these can be applied in personalized lifestyle interventions to improve lifestyle behaviour, body weight management and overall health.

This 2026 update integrates emerging trial evidence — particularly for weight loss and liver disease — to refine EASO’s treatment algorithm for obesity management.

Adipose tissue and skeletal muscle are metabolically active tissues that play a central role in whole-body energy homeostasis. The functionality of these tissues, and hence cardiometabolic health, relies on adequate adjustments in perfusion reflecting metabolic demands in different physiological conditions. Acute exercise increases skeletal muscle perfusion, and this response can be enhanced by prolonged exercise training. Yet, whether similar responses occur in adipose tissue remains unclear. Here, we investigated the effect of a single bout of resistance exercise on adipose tissue microvascular perfusion in healthy older females. Moreover, we explored the effects of 8 weeks of aerobic exercise training on the microvascular perfusion response to acute resistance exercise. Study participants (age: 70 ± 4 y; BMI: 24.7 ± 2.8 kg/m2) were assigned to either a supervised aerobic exercise training (3 times/week) or a no training control group. Before and after the intervention period, microvascular blood volume was measured in femoral adipose tissue and the adjacent skeletal muscle using contrast-enhanced ultrasound. More specifically, the measurements were conducted at rest and at t = 10 and t = 40 min after a single resistance exercise session. We found that microvascular blood volume increased in both adipose (3.0 ± 2.5-fold, p < 0.05) and skeletal muscle (4.5 ± 1.9-fold, p = 0.001) tissue after the resistance exercise session. Eight weeks of aerobic exercise training improved adipose tissue microvascular perfusion after acute resistance exercise compared to the control group (time x group, p = 0.033), without significant within-group changes. The present findings indicate that microvascular blood volume in femoral adipose tissue increases after an acute bout of resistance exercise and may be enhanced following exercise training in healthy older females.

BACKGROUND:Precision nutrition strategies can be effective in optimizing health outcomes. We previously showed that dietary macronutrient modulation targeting tissue-specific insulin resistance (IR) phenotypes induced pronounced improvements in cardiometabolic health. It remains unclear whether these improvements may partially be explained by gut microbiota-related mechanisms. OBJECTIVES:We investigated whether 12-wk high monounsaturated fatty acid (HMUFA) and low-fat, high-protein, high-fiber diets (LFHP) impact gut microbiota composition and functionality in people with predominant muscle IR (MIR) compared with liver IR (LIR) in relation to cardiometabolic health improvements. METHODS:This 2-center, randomized, double-blind, dietary intervention trial included 179 individuals with LIR or MIR [40‒75 y, body mass index (in kg/m2) 25‒40], who followed either a 12-wk isocaloric HMUFA or LFHP diet. A 7-point oral glucose tolerance test was performed to determine tissue-specific IR and cardiometabolic risk factors. Fecal microbiota composition was profiled using 16S ribosomal ribonucleic acid amplicon sequencing (V3‒V4 region), and GLP-1 and gut microbial products were determined in plasma and feces. RESULTS:The HMUFA diet induced significant shifts in overall gut microbial composition (P < 0.05) and short-chain fatty acid-producing bacteria (q < 0.05) in the LIR phenotype, but not in MIR. The LFHP diet induced only modest changes in gut microbiota features. We found phenotype-specific correlations between specific baseline taxa abundance and change in metabolic outcomes (MIR-HMUFA: Barnesiella-ΔMISI (Spearman ρ = 0.45, P < 0.001); LIR-HMUFA: Sutterella-Δplasma-C-reactive protein (Spearman ρ = 0.57, P = 0.0001) and a Rhodospirillales genus-Δhomeostasis model assessment of insulin resistance (Spearman ρ = ‒0.58, P < 0.001). CONCLUSIONS:Individuals with predominant LIR seem more prone to diet-induced gut microbiota-related improvements in cardiometabolic health than those with MIR, highlighting the importance of understanding heterogeneity in IR. Our findings support a role for the gut microbiota in precision nutrition targeting tissue-specific IR. CLINICALTRIALS:gov registration: This is a secondary analysis of the PERSonalized glucose Optimization through Nutritional intervention (PERSON) randomized trial. REGISTRATION NUMBER:NCT03708419, https://clinicaltrials.gov/study/NCT03708419.

The relationship between dietary patterns (DPs) and type 2 diabetes is well established, but the potential role of tissue-specific insulin resistance (IR) in this association remains unclear. This study aimed to derive DPs using reduced rank regression (RRR), incorporating hepatic IR index (HIRI) and muscle insulin sensitivity index (MISI) as response variables. We also examined whether these patterns are associated with insulin sensitivity and pancreatic β-cell function. We conducted a cross-sectional analysis of 700 adults with overweight or obesity participating in the screening phase of the PERSON study. Dietary intakes were assessed using a food frequency questionnaire. RRR was used to derive DPs based on HIRI and MISI. Associations with HOMA-IR, HOMA-β, Matsuda index and Disposition index were tested using multiple regression models adjusted for socio-demographic and lifestyle factors. One DP was retained, explaining 13.7 https://clinicaltrials.gov/study/NCT03708419 (identifier NCT03708419).

OBJECTIVE:We previously identified distinct muscle and liver insulin resistance (IR) metabotypes in middle-aged and older adults. The PERSON study showed that a low-fat, high-protein, high-fiber diet benefits the muscle IR group, while a high-monounsaturated fatty acid diet benefits the liver IR group. We also developed the MetaboHealth score, reflecting risks of mortality, frailty, and cognitive decline. This study aimed to examine whether MetaboHealth interacts with IR metabotypes to influence (i) cardiometabolic health and (ii) body composition outcomes in the PERSON study, informing precision nutrition strategies. METHODS:In total, 242 adults aged 40-75 with IR were randomized to follow an isocaloric low-fat, high-protein, high-fiber or high-monounsaturated fatty acid diet for 12 weeks. Of these, 184 with complete data were grouped into MetaboHealth tertiles (higher = poorer health). Outcomes included a 7-point oral glucose tolerance test and DXA-based body composition. Linear mixed models assessed four-way interactions. RESULTS:No interaction was observed for cardiometabolic outcomes. Significant interactions were found for android, gynoid, total fat percentage, and fat mass index. In the healthiest tertile, matched diets led to greater fat loss. In the poorest tertile, both diets were similarly effective. MetaboHealth remained unchanged. CONCLUSIONS:Combining metabotype with MetaboHealth may enhance personalized dietary strategies for fat loss in insulin-resistant adults.

AIMS:Individuals with liver insulin-resistant (LIR) or muscle insulin-resistant (MIR) phenotypes may respond differently to dietary interventions. Given the interaction between insulin resistance and cardiovascular risk, this sub-analysis of the PERSON study examined whether a personalized diet according to MIR or LIR phenotypes improves vascular function and cardiovascular disease risk factors. MATERIALS AND METHODS:We randomized 119 participants to a 12-week low-fat, high-protein, high-fibre diet (LFHP; may be optimal for LIR) or Mediterranean diet (high in monounsaturated fat, HMUFA; may be optimal for MIR). Randomization linked the insulin-resistant (IR) phenotype to the proposed optimal diet, leading to PhenoDiet A (MIR-HMUFA and LIR-LFHP) and PhenoDiet B (MIR-LFHP and LIR-HMUFA). Before and after the intervention, vascular function (carotid artery reactivity) and cardiovascular risk factors (blood pressure, total cholesterol, HDL-cholesterol and Framingham risk score) were examined. A 7-point oral glucose tolerance test was performed to determine insulin resistance (Matsuda index and HOMA-IR) and disposition index. RESULTS:Following drop-out (n = 18), 101 participants finished the intervention (54 women, 61 ± 7 years, 27.6 [26.4;30.0] kg/m2), with n = 80 available for the primary outcome of vascular function. Overall, the dietary interventions significantly decreased blood pressure, total cholesterol, HDL-cholesterol and the Framingham risk score (all p < 0.05), while vascular function was not affected (p = 0.485). Insulin resistance (p ≤ 0.001), but not disposition index (p = 0.362), was significantly improved after intervention. The Matsuda index (p = 0.078) tended to increase more and total cholesterol (p = 0.052) tended to decrease more in PhenoDiet group B than A, but other changes in outcome parameters were not significantly different between PhenoDiet groups. The LFHP diet resulted in more pronounced improvements in cholesterol, diastolic blood pressure (DBP) and insulin resistance compared with the HMUFA diet (all p < 0.05). CONCLUSION:A 12-week diet improves metabolic and cardiovascular outcomes, but not vascular function in insulin-resistant adults with overweight or obesity. Whilst the LFHP diet resulted in greater improvements in cardiometabolic risk markers than the HMUFA diet, we found no significant differences between the PhenoDiet groups.

Consumption of sweeteners and sweetness enhancers (S SEs) is a popular strategy to reduce sugar intake, but the role of S SEs in body weight regulation and gut microbiota composition remains debated. Here, we show that S SEs in a healthy diet support weight loss maintenance and beneficial gut microbiota shifts in adults with overweight or obesity. In this multi-centre, randomized, controlled trial, we included 341 adults and 38 children with overweight or obesity. Adults followed a 2-month low-energy diet for ≥5 NCT04226911 . The SWEET project is a multicenter, randomized, controlled trial that shows that long-term consumption of sweeteners and sweetness enhancers improves body weight control and elicits beneficial gut microbiota changes in adults with overweight or obesity.

Obesity and associated complications can be managed by obesity medications, prompting the revision of criteria for the diagnosis and staging of this disease.

CONTEXT:Fetuin B is a steatosis-responsive hepatokine that induces glucose intolerance in mice. Recently, we found that fetuin B in white adipose tissue was positively associated with peripheral insulin resistance in mice and a small study population, possibly through a fetuin B-induced inflammatory response in adipocytes. OBJECTIVE:This translational study aimed to investigate the link between plasma fetuin B and the adipose tissue transcriptome and plasma proteome in a large cohort of humans. METHODS:Continuous linear regression analysis in R was applied to investigate the link between plasma fetuin B and the adipose tissue transcriptome (n = 207) and plasma proteome (n = 558) in humans, after adjustment for sex, age, and study center (model 1); model 1 + BMI (model 2); and model 2 + insulin sensitivity (Matsuda index) (model 3). RESULTS:Plasma fetuin B was associated with more than 100 genes in white adipose tissue, belonging to pathways related to cytokine/chemokine signaling (models 1 and 2) and insulin signaling (all models), and with more than 146 plasma proteins involved in pathways related to metabolic processes and insulin signaling (all models). CONCLUSION:Plasma fetuin B is related to adipose tissue genes and plasma proteins involved in metabolic processes and insulin signaling. Our findings provide evidence for the involvement of white adipose tissue in fetuin B-induced insulin resistance.

Introduction: The aim of this study was to describe the design and methodological aspects of the upcoming European Association for the Study of Obesity (EASO) Framework for the Pharmacological Treatment of Obesity utilizing currently available evidence, which is grounded in a rigorous and transparent approach to evidence synthesis and guideline development. Methods: An expert panel of 13 members, selected by EASO, has developed the framework using the GRADE methodology to ensure transparent, evidence-based guideline development. Clinical questions were formulated using the population, intervention, comparator, outcomes (PICO) framework, focusing on the effectiveness and safety of European Medicines Agency-approved obesity management medications, including orlistat, naltrexone/bupropion, liraglutide, semaglutide, and tirzepatide. A comprehensive literature search is being conducted using Medline and Embase, including randomized controlled trials with a minimum duration of 48 weeks. Meta-analyses and network meta-analyses are planned to compare treatment effectiveness and safety profiles across various patient subgroups. The guidelines will target adults with a body mass index (BMI) ≥27 kg/m2 and at least one weight-related comorbidity or a BMI ≥30 kg/m2. The primary endpoint will be total body weight loss. Secondary outcomes include changes in body composition (i.e., fat mass, fat-free mass), metabolic improvements (i.e., glucose levels, HbA1c, lipid profile), remission of obesity-related comorbidities (i.e., type 2 diabetes, obstructive sleep apnea syndrome, metabolic dysfunction-associated steatotic liver disease, cardiovascular disease, and knee osteoarthritis), and improvements in mental health and quality of life. The methodological framework ensures that recommendations are tailored, evidence-based, and applicable across clinical settings. Conclusions: The EASO framework provides a structured and individualized approach to optimize pharmacological treatment for obesity. Its methodological rigor, based on GRADE and PICO, enhances the reliability, reproducibility, and clinical relevance of the guidelines. By integrating clinical efficacy, safety outcomes, and patient-specific factors, this framework offers solid, actionable guidance to support healthcare professionals in delivering high-quality, personalized obesity care. .

This systematic review and network meta-analysis evaluated the efficacy and safety of obesity management medications (OMMs) in terms of reducing body weight and impact on obesity-related complications. Here a Medline and Embase search was performed up to 31 January 2025 for randomized controlled trials comparing OMMs versus placebo/active comparators in adults. Primary endpoint was percentage of total body weight loss (TBWL%) at the end of the study. Secondary endpoints were TBWL% at 1, 2 and ≥3 years, lipid profile, blood pressure, hemoglobin A1c, fasting plasma glucose, mental health, serious adverse events, quality of life, cardiovascular morbidity and mortality, remission of obesity-related complications and all-cause mortality. Fifty-six clinical trials were identified-orlistat (22), semaglutide (14), liraglutide (11), tirzepatide (6), naltrexone/bupropion (5) and phentermine/topiramate (2)-enrolling 60,307 patients (32,598 OMM and 27,709 placebo). All OMMs showed a significantly greater TBWL% versus placebo (P < 0.0001), more than 10% for semaglutide and tirzepatide. Both tirzepatide and semaglutide showed normoglycemia restoration, remission of type 2 diabetes and reduction in hospitalization due to heart failure. Semaglutide was effective in reducing major adverse cardiovascular events and reducing pain in knee osteoarthritis. Tirzepatide was effective in remission of obstructive sleep apnea syndrome and metabolic dysfunction-associated steatohepatitis. These results support the need to individualize the selection of OMMs.

Insulin resistance (IR) is an early marker of cardiometabolic deterioration which may develop heterogeneously in key metabolic organs, including the liver (LIR) and skeletal muscle (MIR). This tissue-specific IR is characterized by distinct metabolic signatures, but the role of the gut microbiota in its etiology remains unclear. Here, we profiled the gut microbiota, its metabolites and the plasma metabolome in individuals with either a LIR or MIR phenotype (n = 233). We observed distinct microbial community structures LIR and MIR, and higher short-chain fatty acid (SCFA) producing bacteria, fecal SCFAs and branched-chain fatty acids and a higher postprandial plasma glucagon-like-peptide-1 response in LIR. In addition, we found variations in metabolome profiles and phenotype-specific associations between microbial taxa and functional metabolite groups. Overall, our study highlights association between gut microbiota and its metabolites composition with IR heterogeneity that can be targeted in precision-based strategies to improve cardiometabolic health. Clinicaltrials.gov registration: NCT03708419.

Obesity is a complex, multifactorial, chronic disease that acts as a gateway to a range of other diseases. Evidence from recent studies suggests that changes in oxygen availability in the microenvironment of metabolic organs may exert an important role in the development of obesity-related cardiometabolic complications. In this review, we will first discuss results from observational and controlled laboratory studies that examined the relationship between reduced oxygen availability and obesity-related metabolic derangements. Next, the effects of alterations in oxygen partial pressure (pO2) in the adipose tissue, skeletal muscle and the liver microenvironment on physiological processes in these key metabolic organs will be addressed, and how this might relate to cardiometabolic complications. Since many obesity-related chronic diseases, including type 2 diabetes mellitus, cardiovascular diseases, chronic kidney disease, chronic obstructive pulmonary disease and obstructive sleep apnea, are characterized by changes in pO2 in the tissue microenvironment, a better understanding of the metabolic impact of altered tissue oxygenation can provide valuable insights into the complex interplay between environmental and biological factors involved in the pathophysiology of metabolic impairments. This may ultimately contribute to the development of novel strategies to prevent and treat obesity-related cardiometabolic diseases.

Duration and severity of exposure to excess adipose tissue are important risk factors for complications, but are generally not examined in conjunction. We developed a metric considering both factors to examine the relationship between obesity-related complications and parameters of cardiometabolic health in patients undergoing a metabolic bariatric procedure (MBS). Data from patients screened for primary MBS between 2017 and 2021 were analyzed. The Obesity Exposure score (OBES), based on self-reported years of life with a BMI ≥ 25 kg/m2, was calculated with increased weighting applied for higher BMI categories. Multivariate logistic regression analysis was performed, adjusting for multiple potential confounders. In total, 2441 patients were included (76

OBJECTIVE:Induction of browning in white adipose tissue (WAT) increases energy expenditure and may be an attractive target for the treatment of obesity. Since activation of Fas (CD95) induces pathways known to blunt expression of uncoupling protein 1 (UCP1), we hypothesized that Fas expression in adipocytes inhibits WAT browning and thus contributes to the development of obesity. METHODS:Adipocyte-specific Fas knockout (FasΔadipo) and control littermate (FasF/F) mice were fed a regular chow diet or a high-fat diet (HFD) for 20 weeks. Energy expenditure was assessed by indirect calorimetry, and browning was determined in subcutaneous WAT. In vitro, UCP1 was analyzed in subcutaneous murine adipocytes treated with or without Fas ligand. Moreover, FAS expression in WAT was correlated to UCP1 and percentage of body fat in human individuals. RESULTS:HFD-fed FasΔadipo mice displayed reduced body weight gain and blunted adiposity compared to control littermates. Concomitantly, whole-body energy expenditure and WAT browning were elevated. In cultured adipocytes, Fas ligand treatment blunted isoproterenol-induced UCP1 protein levels. In support of these findings in rodents, FAS expression in WAT correlated negatively with UCP1 but positively with adiposity in human individuals. CONCLUSIONS:Fas activation in adipocytes contributes to HFD-associated adiposity in rodents and may be a therapeutic target to reduce obesity and associated diseases.