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Succinate is a signaling metabolite sensed extracellularly by succinate receptor 1 (SUNCR1). The accumulation of succinate in macrophages is known to activate a pro-inflammatory program; however, the contribution of SUCNR1 to macrophage phenotype and function has remained unclear. Here we found that activation of SUCNR1 had a critical role in the anti-inflammatory responses in macrophages. Myeloid-specific deficiency in SUCNR1 promoted a local pro-inflammatory phenotype, disrupted glucose homeostasis in mice fed a normal chow diet, exacerbated the metabolic consequences of diet-induced obesity and impaired adipose-tissue browning in response to cold exposure. Activation of SUCNR1 promoted an anti-inflammatory phenotype in macrophages and boosted the response of these cells to type 2 cytokines, including interleukin-4. Succinate decreased the expression of inflammatory markers in adipose tissue from lean human subjects but not that from obese subjects, who had lower expression of SUCNR1 in adipose-tissue-resident macrophages. Our findings highlight the importance of succinate–SUCNR1 signaling in determining macrophage polarization and assign a role to succinate in limiting inflammation. Succinate is a signaling metabolite sensed extracellularly by SUNCR1. Fernandez-Veledo and colleagues show that activation of SUCNR1 promotes an anti-inflammatory phenotype in adipose-tissue macrophages in lean mice and people.

Background Succinate is produced by both human cells and by gut bacteria and couples metabolism to inflammation as an extracellular signaling transducer. Circulating succinate is elevated in patients with obesity and type 2 diabetes and is linked to numerous complications, yet no studies have specifically addressed the contribution of gut microbiota to systemic succinate or explored the consequences of reducing intestinal succinate levels in this setting. Results Using germ-free and microbiota-depleted mouse models, we show that the gut microbiota is a significant source of circulating succinate, which is elevated in obesity. We also show in vivo that therapeutic treatments with selected bacteria diminish the levels of circulating succinate in obese mice. Specifically, we demonstrate that Odoribacter laneus is a promising probiotic based on its ability to deplete succinate and improve glucose tolerance and the inflammatory profile in two independent models of obesity ( db/db mice and diet-induced obese mice). Mechanistically, this is partly mediated by the succinate receptor 1. Supporting these preclinical findings, we demonstrate an inverse correlation between plasma and fecal levels of succinate in a cohort of patients with severe obesity. We also show that plasma succinate, which is associated with several components of metabolic syndrome including waist circumference, triglycerides, and uric acid, among others, is a primary determinant of insulin sensitivity evaluated by the euglycemic-hyperinsulinemic clamp. Conclusions Overall, our work uncovers O. laneus as a promising next-generation probiotic to deplete succinate and improve glucose tolerance and obesity-related inflammation. 3xBZTCGcPCuPE54e-xtBbB Video Abstract

Pancreatic β cell dysfunction is a key feature of type 2 diabetes, and novel regulators of insulin secretion are desirable. Here, we report that succinate receptor 1 (SUCNR1) is expressed in β cells and is upregulated in hyperglycemic states in mice and humans. We found that succinate acted as a hormone-like metabolite and stimulated insulin secretion via a SUCNR1-Gq-PKC–dependent mechanism in human β cells. Mice with β cell–specific Sucnr1 deficiency exhibited impaired glucose tolerance and insulin secretion on a high-fat diet, indicating that SUCNR1 is essential for preserving insulin secretion in diet-induced insulin resistance. Patients with impaired glucose tolerance showed an enhanced nutrition-related succinate response, which correlates with the potentiation of insulin secretion during intravenous glucose administration. These data demonstrate that the succinate/SUCNR1 axis is activated by high glucose and identify a GPCR-mediated amplifying pathway for insulin secretion relevant to the hyperinsulinemia of prediabetic states.

Background Succinate is produced by both host and microbiota, with a key role in the interplay of immunity and metabolism and an emerging role as a biomarker for inflammatory and metabolic disorders in middle-aged adults. The relationship between plasma succinate levels and cardiovascular disease (CVD) risk in young adults is unknown. Methods Cross-sectional study in 100 (65% women) individuals aged 18–25 years from the ACTIvating Brown Adipose Tissue through Exercise (ACTIBATE) study cohort. CVD risk factors, body composition, dietary intake, basal metabolic rate, and cardiorespiratory fitness were assessed by routine methods. Plasma succinate was measured with an enzyme-based assay. Brown adipose tissue (BAT) was evaluated by positron emission tomography, and circulating oxylipins were assessed by targeted metabolomics. Fecal microbiota composition was analyzed in a sub-sample. Results Individuals with higher succinate levels had higher levels of visceral adipose tissue (VAT) mass (+ 42.5%), triglycerides (+ 63.9%), C-reactive protein (+ 124.2%), diastolic blood pressure (+ 5.5%), and pro-inflammatory omega-6 oxylipins than individuals with lower succinate levels. Succinate levels were also higher in metabolically unhealthy individuals than in healthy overweight/obese peers. Succinate levels were not associated with BAT volume or activity or with fecal microbiota composition and diversity. Conclusions Plasma succinate levels are linked to a specific pro-inflammatory omega-6 signature pattern and higher VAT levels, and seem to reflect the cardiovascular status of young adults.

Adipose-derived mesenchymal stem cells (ASCs) are a promising option for the treatment of obesity and its metabolic co-morbidities. Despite the recent identification of brown adipose tissue (BAT) as a potential target in the management of obesity, the use of ASCs isolated from BAT as a therapy for patients with obesity has not yet been explored. Metabolic activation of BAT has been shown to have not only thermogenic effects, but it also triggers the secretion of factors that confer protection against obesity. Herein, we isolated and characterized ASCs from the visceral adipose tissue surrounding a pheochromocytoma (IB-hASCs), a model of inducible BAT in humans. We then compared the anti-obesity properties of IB-hASCs and human ASCs isolated from visceral white adipose tissue (W-hASCs) in a murine model of diet-induced obesity. We found that both ASC therapies mitigated the metabolic abnormalities of obesity to a similar extent, including reducing weight gain and improving glucose tolerance. However, infusion of IB-hASCs was superior to W-hASCs in suppressing lipogenic and inflammatory markers, as well as preserving insulin secretion. Our findings provide evidence for the metabolic benefits of visceral ASC infusion and support further studies on IB-hASCs as a therapeutic option for obesity-related comorbidities.

Dysfunctional adipocyte precursors have emerged as key determinants for obesity‐ and aging‐related inflammation, but the mechanistic basis remains poorly understood. Here, we explored the dysfunctional adipose tissue of elderly and obese individuals focusing on the metabolic and inflammatory state of human adipose‐derived mesenchymal stromal cells (hASCs), and on sirtuins, which link metabolism and inflammation. Both obesity and aging impaired the differentiation potential of hASCs but had a different impact on their proliferative capacity. hASCs from elderly individuals (≥65 years) showed an upregulation of glycolysis‐related genes, which was accompanied by increased lactate secretion and glycogen storage, a phenotype that was exaggerated by obesity. Multiplex protein profiling revealed that the metabolic switch to glycogenesis was associated with a pro‐inflammatory secretome concomitant with a decrease in the protein expression of SIRT1 and SIRT6. siRNA‐mediated knockdown of SIRT1 and SIRT6 in hASCs from lean adults increased the expression of pro‐inflammatory and glycolysis‐related markers, and enforced glycogen deposition by overexpression of protein targeting to glycogen (PTG) led to a downregulation of SIRT1/6 protein levels, mimicking the inflammatory state of hASCs from elderly subjects. Overall, our data point to a glycogen‐SIRT1/6 signaling axis as a driver of age‐related inflammation in adipocyte precursors. Glycogen deposition in adipocyte precursors as a driver of inflammation through a SIRT1/6‐dependent mechanism. Both aging and obesity impact the metabolic and inflammatory properties of adipocyte precursors. A novel pathway linking metabolic dysregulation and inflammation is shown.

Background Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic condition characterized by hepatic fat accumulation and systemic metabolic dysfunction. MASLD exhibits clear sex differences, yet the mechanisms underlying these disparities remain poorly defined. Methods To investigate the early temporal dynamics of MASLD, male and female mice were fed a choline-deficient, methionine-restricted (0.1%) high-fat (61%) diet (CDAHFD; characterized by impaired hepatic lipid export and enhanced lipotoxic stress) for two weeks, enabling assessment of initial metabolic responses. Results Despite their presumed protection, females developed an exacerbated hepatic phenotype accompanied by intestinal remodeling and compromised barrier integrity. In contrast, males displayed early weight loss and improved glucose tolerance, alongside reduced hepatic transcriptional changes indicative of adaptive metabolism. Additionally, sex-specific hypothalamic responses were observed, with males showing reduced expression of microglial homeostatic markers, increased inflammation, and alterations in energy balance-related signaling, consistent with neuroimmune modulation. These responses were paralleled by sex-dependent alterations in adipose tissue, including early adipocyte remodeling and distinct transcriptional changes, which were predominantly consistent with baseline sex differences and therefore suggest a limited contribution of this tissue to the early diet-induced metabolic divergence. Importantly, these early sex-dependent adaptations were not sustained over time, as prolonged CDAHFD (14 weeks) resulted in a shift towards a more sever inflammatory and fibrotic hepatic phenotype in males, while females exhibited relative preservation of hepatic metabolic function and attenuation of intestinal alterations. Conclusions These findings demonstrate that sexual dimorphism in MASLD arises early and evolves dynamically, with females mounting an acute metabolic and intestinal stress response, whereas males activate compensatory pathways that preserve metabolic homeostasis. These results highlight sex-specific trajectory in MASLD progression and emphasize the need for integrative approaches to unravel its pathophysiology. Highlights Females develop more early severe liver damage, accompanied by pronounced intestinal alterations and impaired gut barrier integrity under a choline-deficient, methionine-restricted high-fat diet (CDAHFD). Males show early body weight loss, improved glucose tolerance, and reduced liver gene expression modifications in response to CDAHFD. CDAHFD elicits sex-specific central and peripheral adaptations, including altered hypothalamic neuroimmune signaling and adipose tissue transcriptional remodeling. Findings reveal that sex differences in MASLD appear early and progress along distinct biological pathways. Plain english summary Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common liver disorder where fat builds up in the liver and disrupts overall metabolism. It is known that men and women experience this disease differently, but the reasons for these differences are still unclear. To explore this, researchers studied male and female mice that were fed a special diet designed to cause early liver stress. Surprisingly, the female mice showed more severe liver changes than the males, even though females are often thought to be protected against such damage. The females also showed signs of intestinal changes and a weakened gut barrier, suggesting their bodies were under higher stress. In contrast, male mice lost weight, had better blood sugar control, and showed reduced changes in the liver, which suggested that their bodies were adapting to the diet rather than being harmed by it. These differences were also linked to changes in the brain areas that control appetite, energy use, and inflammation. Overall, this study shows that sex differences in MASLD appear very early and follow different paths. Females respond with stronger stress and intestinal reactions, while males seem to trigger protective mechanisms. Understanding these early sex-specific patterns could help guide the development of better treatments for both men and women with liver disease.

Evidence from mouse models suggests that zinc-α2-glycoprotein (ZAG) is a novel anti-obesity adipokine. In humans, however, data are controversial and its physiological role in adipose tissue (AT) remains unknown. Here we explored the molecular mechanisms by which ZAG regulates carbohydrate metabolism in human adipocytes. ZAG action on glucose uptake and insulin action was analyzed. β1 and β2-adrenoreceptor (AR) antagonists and siRNA targeting PP2A phosphatase were used to examine the mechanisms by which ZAG modulates insulin sensitivity. Plasma levels of ZAG were measured in a lean patient cohort stratified for HOMA-IR. ZAG treatment increased basal glucose uptake, correlating with an increase in GLUT expression, but induced insulin resistance in adipocytes. Pretreatment of adipocytes with propranolol and a specific β1-AR antagonist demonstrated that ZAG effects on basal glucose uptake and GLUT4 expression are mediated via β1-AR, whereas inhibition of insulin action is dependent on β2-AR activation. ZAG treatment correlated with an increase in PP2A activity. Silencing of the PP2A catalytic subunit abrogated the negative effect of ZAG on insulin-stimulated AKT phosphorylation and glucose uptake but not on GLUT4 expression and basal glucose uptake. ZAG circulating levels were unchanged in a lean patient cohort stratified for HOMA-IR. Neither glucose nor insulin was associated with plasma ZAG. ZAG inhibits insulin-induced glucose uptake in human adipocytes by impairing insulin signaling at the level of AKT in a β2-AR- and PP2A-dependent manner.

BackgroundA functional population of adipocyte precursors, termed adipose-derived stromal/stem cells (ASCs), is crucial for proper adipose tissue (AT) expansion, lipid handling, and prevention of lipotoxicity in response to chronic positive energy balance. We previously showed that obese human subjects contain a dysfunctional pool of ASCs. Elucidation of the mechanisms underlying abnormal ASC function might lead to therapeutic interventions for prevention of lipotoxicity by improving the adipogenic capacity of ASCs.MethodsUsing epigenome-wide association studies, we explored the impact of obesity on the methylation signature of human ASCs and their differentiated counterparts. Mitochondrial phenotyping of lean and obese ASCs was performed. TBX15 loss- and gain-of-function experiments were carried out and western blotting and electron microscopy studies of mitochondria were performed in white AT biopsies from lean and obese individuals.ResultsWe found that DNA methylation in adipocyte precursors is significantly modified by the obese environment, and adipogenesis, inflammation, and immunosuppression were the most affected pathways. Also, we identified TBX15 as one of the most differentially hypomethylated genes in obese ASCs, and genetic experiments revealed that TBX15 is a regulator of mitochondrial mass in obese adipocytes. Accordingly, morphological analysis of AT from obese subjects showed an alteration of the mitochondrial network, with changes in mitochondrial shape and number.ConclusionsWe identified a DNA methylation signature in adipocyte precursors associated with obesity, which has a significant impact on the metabolic phenotype of mature adipocytes.