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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. [ABSTRACT FROM AUTHOR]

Objective: Fetuin B is a steatosis‐responsive hepatokine that causes glucose intolerance in mice, but the underlying mechanisms remain incompletely described. This study aimed to elucidate the mechanisms of action of fetuin B by investigating its putative effects on white adipose tissue metabolism. Methods: First, fetuin B gene and protein expression was measured in multiple organs in mice and in cultured adipocytes. Next, the authors performed a hyperinsulinemic‐euglycemic clamp in mice and in humans to examine the link between white adipose tissue fetuin B content and indices of insulin sensitivity. Finally, the effect of fetuin B on inflammation was investigated in cultured adipocytes by quantitative polymerase chain reaction and full RNA sequencing. Results: This study demonstrated in adipocytes and mice that fetuin B was produced and secreted by the liver and taken up by adipocytes and adipose tissue. There was a strong negative correlation between white adipose tissue fetuin B content and peripheral insulin sensitivity in mice and in humans. RNA sequencing and polymerase chain reaction analysis revealed that fetuin B induced an inflammatory response in adipocytes. Conclusions: Fetuin B content in white adipose tissue strongly associated with peripheral insulin resistance in mice and humans. Furthermore, fetuin B induced a proinflammatory response in adipocytes, which might drive peripheral insulin resistance. [ABSTRACT FROM AUTHOR]

Objective: This study (1) investigated the effect of weight loss on whole‐body and tissue‐specific insulin sensitivity and on intrahepatic lipid (IHL) content and composition and (2) investigated the association between weight‐loss‐induced changes in insulin sensitivity and IHL content in individuals with overweight or obesity. Methods: In this secondary analysis of the European SWEET project, 50 adults (age 18–65 years) with overweight or obesity (BMI ≥ 25 kg/m2) followed a low‐energy diet (LED) for 2 months. At baseline and after the LED, body composition (dual‐energy x‐ray absorptiometry), IHL content and composition (proton magnetic resonance spectroscopy), whole‐body insulin sensitivity (Matsuda index), muscle insulin sensitivity index (MISI), and hepatic insulin resistance index (HIRI) were determined (7‐point oral glucose tolerance test). Results: The LED reduced body weight (p < 0.001). This was accompanied by increased Matsuda index and reduced HIRI (both p < 0.001) but no change in MISI (p = 0.260). Weight loss decreased IHL content (mean [SEM], 3.9% [0.7%] vs. 1.6% [0.5%], p < 0.001) and the hepatic saturated fatty acid fraction (41.0% [1.5%] vs. 36.6% [1.9%], p = 0.039). The reduced IHL content was associated with an improvement in HIRI (r = 0.402, p = 0.025). Conclusions: Weight loss decreased IHL content and the hepatic saturated fatty acid fraction. The decrease in IHL content was associated with weight‐loss‐induced improvement in hepatic insulin sensitivity in individuals with overweight or obesity. [ABSTRACT FROM AUTHOR]

Objective: A proinflammatory adipose tissue (AT) microenvironment and systemic low‐grade inflammation may differentially affect tissue‐specific insulin sensitivity. This study investigated the relationships of abdominal subcutaneous AT (aSAT) and circulating immune cells, aSAT gene expression, and circulating inflammatory markers with liver and skeletal muscle insulin sensitivity in people with overweight and obesity. Methods: Individuals with overweight and obesity from the PERSonalized Glucose Optimization Through Nutritional Intervention (PERSON) Study (n = 219) and the Maastricht Study (replication cohort; n = 1256) underwent a seven‐point oral glucose tolerance test to assess liver and muscle insulin sensitivity, and circulating inflammatory markers were determined. In subgroups, flow cytometry was performed to identify circulating and aSAT immune cells, and aSAT gene expression was evaluated. Results: The relative abundances of circulating T cells, nonclassical monocytes, and CD56dim CD16+ natural killer cells were inversely associated with liver, but not muscle, insulin sensitivity in the PERSON Study. The inverse association between circulating (classical) monocytes and liver insulin sensitivity was confirmed in the Maastricht Study. In aSAT, immune cell populations were not related to insulin sensitivity. Furthermore, aSAT gene expression of interleukin 6 and CD14 was positively associated with muscle, but not liver, insulin sensitivity. Conclusions: The present findings demonstrate that circulating immune cell populations and inflammatory gene expression in aSAT show distinct associations with liver and muscle insulin sensitivity. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study is to investigate associations between the physical activity (PA) spectrum (sedentary behavior to exercise) and tissue‐specific insulin resistance (IR). Methods: We included 219 participants for analysis (median [IQR]: 61 [55; 67] years, BMI 29.6 [26.9; 32.0] kg/m2; 60% female) with predominant muscle or liver IR, as determined using a 7‐point oral glucose tolerance test (OGTT). PA and sedentary behavior were measured objectively (ActivPAL) across 7 days. Context‐specific PA was assessed with the Baecke questionnaire. Multiple linear regression models (adjustments include age, sex, BMI, site, season, retirement, and dietary intake) were used to determine associations between the PA spectrum and hepatic insulin resistance index (HIRI), muscle insulin sensitivity index (MISI) and whole‐body IR (HOMA‐IR, Matsuda index). Results: In fully adjusted models, objectively measured total PA (standardized regression coefficient β = 0.17, p = 0.020), light‐intensity PA (β = 0.15, p = 0.045) and moderate‐to‐vigorous intensity PA (β = 0.13, p = 0.048) were independently associated with Matsuda index, but not HOMA‐IR (p > 0.05). A higher questionnaire‐derived sport index and leisure index were associated with significantly lower whole‐body IR (Matsuda, HOMA‐IR) in men but not in women. Results varied across tissues: more time spent sedentary (β = −0.24, p = 0.045) and a higher leisure index (β = 0.14, p = 0.034) were respectively negatively and positively associated with MISI, but not HIRI. A higher sport index was associated with lower HIRI (β = −0.30, p = 0.007, in men only). Conclusion: While we confirm a beneficial association between PA and whole‐body IR, our findings indicate that associations between the PA spectrum and IR seem distinct depending on the primary site of insulin resistance (muscle or liver). [ABSTRACT FROM AUTHOR]

Objective: Severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) uses the host's angiotensin‐converting enzyme 2 (ACE2) as a cellular entry point. Therefore, modulating ACE2 might impact SARS‐CoV‐2 viral replication, shedding, and coronavirus disease 2019 (COVID‐19) severity. Here, it was investigated whether the angiotensin II type 1 receptor blocker valsartan alters the expression of renin‐angiotensin system (RAS) components, including ACE2, in human adipose tissue (AT) and skeletal muscle. Methods: A randomized, double‐blind, placebo‐controlled clinical trial was performed, in which 36 participants (BMI 31.0 ± 0.8 kg/m2) with impaired glucose metabolism received either valsartan or placebo for 26 weeks. Before and after 26 weeks' treatment, abdominal subcutaneous AT and skeletal muscle biopsies were obtained, and gene expression of RAS components was measured by quantitative reverse transcription polymerase chain reaction. Results: Valsartan treatment did not significantly impact the expression of RAS components, including ACE2, in AT and skeletal muscle. Conclusions: Given the pivotal role of ACE2 in SARS‐CoV‐2 spread and the clinical outcomes in COVID‐19 patients, the data suggest that the putative beneficial effects of angiotensin II type 1 receptor blockers on the clinical outcomes of patients with COVID‐19 may not be mediated through altered ACE2 expression in abdominal subcutaneous AT. [ABSTRACT FROM AUTHOR]

Key points: We determined if bed rest increased mitochondrially derived reactive oxygen species and cellular redox stress, contributing to the induction of insulin resistance.Bed rest decreased maximal and submaximal ADP‐stimulated mitochondrial respiration.Bed rest did not alter mitochondrial H2O2 emission in the presence of ADP concentrations indicative of resting muscle, the ratio of H2O2 emission to mitochondrial O2 consumption or markers of oxidative stressThe present data suggest strongly that mitochondrial H2O2 does not contribute to bed rest‐induced insulin resistance Mitochondrial H2O2 has been causally linked to diet‐induced insulin resistance, although it remains unclear if muscle disuse similarly increases mitochondrial H2O2. Therefore, we investigated the potential that an increase in skeletal muscle mitochondrial H2O2 emission, potentially as a result of decreased ADP sensitivity, contributes to cellular redox stress and the induction of insulin resistance during short‐term bed rest in 20 healthy males. Bed rest led to a decline in glucose infusion rate during a hyperinsulinaemic‐euglycaemic clamp (−42 ± 2%; P < 0.001), and in permeabilized skeletal muscle fibres it decreased OXPHOS protein content (−16 ± 8%) and mitochondrial respiration across a range of ADP concentrations (−13 ± 5%). While bed rest tended to increase maximal mitochondrial H2O2 emission rates (P = 0.053), H2O2 emission in the presence of ADP concentrations indicative of resting muscle, the ratio of H2O2 emission to mitochondrial O2 consumption, and markers of oxidative stress were not altered following bed rest. Altogether, while bed rest impairs mitochondrial ADP‐stimulated respiration, an increase in mitochondrial H2O2 emission does not contribute to the induction of insulin resistance following short‐term bed rest. Key points: We determined if bed rest increased mitochondrially derived reactive oxygen species and cellular redox stress, contributing to the induction of insulin resistance.Bed rest decreased maximal and submaximal ADP‐stimulated mitochondrial respiration.Bed rest did not alter mitochondrial H2O2 emission in the presence of ADP concentrations indicative of resting muscle, the ratio of H2O2 emission to mitochondrial O2 consumption or markers of oxidative stressThe present data suggest strongly that mitochondrial H2O2 does not contribute to bed rest‐induced insulin resistance [ABSTRACT FROM AUTHOR]

Key points: Blood flow restricted resistance exercise (BFR‐RE) is capable of inducing comparable adaptations to traditional resistance exercise (RE), despite a lower total exercise volume.It has been suggested that an increase in reactive oxygen species (ROS) production may be involved in this response; however, oxygen partial pressure (PO2) is reduced during BFR‐RE, and the influence of PO2 on mitochondrial redox balance remains poorly understood.In human skeletal muscle tissue, we demonstrate that both maximal and submaximal mitochondrial ROS emission rates are acutely decreased 2 h following BFR‐RE, but not RE, occurring along with a reduction in tissue oxygenation during BFR‐RE.We further suggest that PO2 is involved in this response because an in vitro analysis revealed that reducing PO2 dramatically decreased mitochondrial ROS emissions and electron leak to ROS.Altogether, these data indicate that mitochondrial ROS emission rates are attenuated following BFR‐RE, and such a response is likely influenced by reductions in PO2. Low‐load blood flow restricted resistance exercise (BFR‐RE) training has been proposed to induce comparable adaptations to traditional resistance exercise (RE) training, however, the acute signalling events remain unknown. Although a suggested mechanism of BFR‐RE is an increase in reactive oxygen species (ROS) production, oxygen partial pressure (PO2) is reduced during BFR‐RE, and the influence of O2 tension on mitochondrial redox balance remains ambiguous. We therefore aimed to determine whether skeletal muscle mitochondrial bioenergetics were altered following an acute bout of BFR‐RE or RE, and to further examine the role of PO2 in this response. Accordingly, muscle biopsies were obtained from 10 males at rest and 2 h after performing three sets of single‐leg squats (RE or BFR‐RE) to failure at 30% one‐repetition maximum. We determined that mitochondrial respiratory capacity and ADP sensitivity were not altered in response to RE or BFR‐RE. Although maximal (succinate) and submaximal (non‐saturating ADP) mitochondrial ROS emission rates were unchanged following RE, BFR‐RE attenuated these responses by ∼30% compared to pre‐exercise, occurring along with a reduction in skeletal muscle tissue oxygenation during BFR‐RE (P < 0.01 vs. RE). In a separate cohort of participants, evaluation of mitochondrial bioenergetics in vitro revealed that mild O2 restriction (50 µm) dramatically attenuated maximal (∼4‐fold) and submaximal (∼50‐fold) mitochondrial ROS emission rates and the fraction of electron leak to ROS compared to room air (200 µm). Combined, these data demonstrate that mitochondrial ROS emissions are attenuated following BFR‐RE, a response which may be mediated by a reduction in skeletal muscle PO2. Key points: Blood flow restricted resistance exercise (BFR‐RE) is capable of inducing comparable adaptations to traditional resistance exercise (RE), despite a lower total exercise volume.It has been suggested that an increase in reactive oxygen species (ROS) production may be involved in this response; however, oxygen partial pressure (PO2) is reduced during BFR‐RE, and the influence of PO2 on mitochondrial redox balance remains poorly understood.In human skeletal muscle tissue, we demonstrate that both maximal and submaximal mitochondrial ROS emission rates are acutely decreased 2 h following BFR‐RE, but not RE, occurring along with a reduction in tissue oxygenation during BFR‐RE.We further suggest that PO2 is involved in this response because an in vitro analysis revealed that reducing PO2 dramatically decreased mitochondrial ROS emissions and electron leak to ROS.Altogether, these data indicate that mitochondrial ROS emission rates are attenuated following BFR‐RE, and such a response is likely influenced by reductions in PO2. [ABSTRACT FROM AUTHOR]

Adipose tissue (AT) dysfunction contributes to the pathophysiology of insulin resistance and type 2 diabetes. Previous studies have shown that altered AT oxygenation affects adipocyte functionality, but it remains to be elucidated whether altered AT oxygenation is more strongly related to obesity or insulin sensitivity. In the present study, we tested the hypothesis that AT oxygenation is associated with insulin sensitivity rather than adiposity in humans. Thirty‐five lean and obese individuals (21 men and 14 women, aged 40‐65 years) with either normal or impaired glucose metabolism participated in a cross‐sectional single‐centre study. We measured abdominal subcutaneous AT oxygenation, body composition and insulin sensitivity. AT oxygenation was higher in obese insulin resistant as compared to obese insulin sensitive (IS) individuals with similar age, body mass index and body fat percentage, both in men and women. No significant differences in AT oxygenation were found between obese IS and lean IS men. Moreover, AT oxygenation was positively associated with insulin resistance (r = 0.465; P = .005), even after adjustment for age, sex and body fat percentage (standardized β = 0.479; P = .005). In conclusion, abdominal subcutaneous AT oxygenation is associated with insulin sensitivity both in men and women, independently of adiposity. AT oxygenation may therefore be a promising target to improve insulin sensitivity. [ABSTRACT FROM AUTHOR]

To investigate the association between muscle fiber capillarization and indices of insulin sensitivity in healthy older adults. A skeletal muscle biopsy was taken from the m. vastus lateralis of 22 healthy (nondiabetic) male older adults. In addition, all participants underwent an Oral Glucose Tolerance Test ( OGTT). Muscle fiber capillarization was assessed by immunohistochemistry. Participants were divided into a group with relatively low ( LOW) or high ( HIGH) muscle fiber capillarization (capillary-to-fiber perimeter exchange ( CFPE) index), based on the median value for the entire group. All participants were healthy, nonobese, and had a normal glucose tolerance, according to the individual OGTT results. Whereas no differences in blood glucose concentrations were observed between groups during the OGTT, the postprandial increase in plasma insulin concentrations was significantly greater in the LOW compared to the HIGH muscle fiber capillarization group ( P < 0.05). Skeletal muscle fiber capillarization may determine insulin sensitivity in humans. [ABSTRACT FROM AUTHOR]

Obesity is a complex disorder of excessive adiposity, and is associated with adverse health effects such as cardiometabolic complications, which are to a large extent attributable to dysfunctional white adipose tissue. Adipose tissue dysfunction is characterized by adipocyte hypertrophy, impaired adipokine secretion, a chronic low‐grade inflammatory status, hormonal resistance and altered metabolic responses, together contributing to insulin resistance and related chronic diseases. Adipose tissue hypoxia, defined as a relative oxygen deficit, in obesity has been proposed as a potential contributor to adipose tissue dysfunction, but studies in humans have yielded conflicting results. Here, we will review the role of adipose tissue oxygenation in the pathophysiology of obesity‐related complications, with a specific focus on human studies. We will provide an overview of the determinants of adipose tissue oxygenation, as well as the role of adipose tissue oxygenation in glucose homeostasis, lipid metabolism and inflammation. Finally, we will discuss the putative effects of physiological and experimental hypoxia on adipose tissue biology and whole‐body metabolism in humans. We conclude that several lines of evidence suggest that alteration of adipose tissue oxygenation may impact metabolic homeostasis, thereby providing a novel strategy to combat chronic metabolic diseases in obese humans. [ABSTRACT FROM AUTHOR]

Obesity is characterized by a blunted lipolytic response in abdominal subcutaneous adipose tissue (SAT) and low circulating vitamin D levels. Here we investigated whether an impaired SAT lipolytic response coincides with an impaired SAT vitamin D release in eight lean and six obese men. 25‐hydroxyvitamin D3 [25(OH)D3] and 1,25‐dihydroxyvitamin D3 [1,25(OH)2D3] fluxes across SAT were measured using arterio‐venous blood sampling in combination with AT blood flow measurements after an overnight fast and during 1‐hr intravenous infusion of the non‐selective ß‐adrenergic agonist isoprenaline (20 ng·kg FFM−1·min−1). 1,25(OH)2D3 was released across abdominal SAT during isoprenaline infusion in lean [−0.01 (−0.04 to 0.00) pmol*100 g tissue−1*min−1, p =.017 vs. zero flux], but not in obese men [0.01 (0.00 to 0.02) pmol*100 g tissue−1*min−1, p =.116 vs. zero flux], and accompanied by an impaired isoprenaline‐induced lipolytic response in abdominal SAT of obese versus lean men. Isoprenaline had no significant effects on net 25(OH)D3 release across abdominal SAT and plasma vitamin D metabolites in lean and obese men. To conclude, a blunted isoprenaline‐mediated lipolysis is accompanied by reduced release of 1,25(OH)2D3 vitamin D across abdominal SAT in obesity. [ABSTRACT FROM AUTHOR]

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/m 2 ), 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., (© 2025 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)