M etabolic syndrome (MetS)1 is a disorder of energy use and storage, diagnosed by co-occurrence of at least 3 of 5 of the following medical conditions: abdominal (central) obesity, hypertension, elevated fasting-plasma glucose, high triglycerides, and low high-density lipoprotein cholesterol levels. Clinically, MetS is strongly associated with increased risk of cardiovascular disease and type-2 diabetes mellitus.Adipose tissue plays a central role in the metabolic alterations: adipose tissue is not only the energy store of the body but also influences food intake, insulin sensitivity and secretion, vascular function, systemic inflammation, and oxidative stress because of its hormonal functions.2 Understanding the molecular mechanisms regulating adipose tissue function and adipokine secretion is becoming increasingly important.The steroid hormone aldosterone (aldo) participates in blood pressure control through regulation of renal salt and water reabsorption via activation of the mineralocorticoid receptor (MR). The MR is a ligand-activated transcription factor with a widespread expression pattern. In the past decade, we and others demonstrated that MR expression and activation lead to major pathophysiological consequences in heart, vessels, brain, eye, and skin, extending the potential therapeutic use of pharmacological MR antagonists.3 These novel nonclassical targets also include adipose tissue where the role of the mineralocorticoid system is still debated. 4 Experimental and clinical studies have shown that aldo excess is a potential risk factor for type-2 diabetes mellitus, through mechanisms independent of its blood pressure effect. A high prevalence (10%-50%) of glucose intolerance or type-2 diabetes mellitus has been reported in primary aldosteronism, and metabolic disturbances are corrected by surgical removal of aldo-producing adenomas.5 Experimental studies performed in various rodent models, that is, db/db, ob/ob, or diet-induced obese mice, proposed a specific role of MR Abstract-Metabolic syndrome is a major risk factor for the development of diabetes mellitus and cardiovascular diseases.Pharmacological antagonism of the mineralocorticoid receptor (MR), a ligand-activated transcription factor, limits metabolic syndrome in preclinical models, but mechanistic studies are lacking to delineate the role of MR activation in adipose tissue. In this study, we report that MR expression is increased in visceral adipose tissue in a preclinical mouse model of metabolic syndrome and in obese patients. In vivo conditional upregulation of MR in mouse adipocytes led to increased weight and fat mass, insulin resistance, and metabolic syndrome features without affecting blood pressure. We identified prostaglandin D2 synthase as a novel MR target gene in adipocytes and AT56, a specific inhibitor of prostaglandin D2 synthase enzymatic activity, blunted adipogenic aldosterone effects. Moreover, translational studies showed that expression of MR and prostaglandin D2 synthase is strongly correlated in adipose tissues fro...