Adipocyte Mineralocorticoid Receptor Activation Leads to Metabolic Syndrome and Induction of Prostaglandin D2 Synthase

Abstract

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...

Adipocyte-Specific Mineralocorticoid Receptor Overexpression in Mice Is Associated With Metabolic Syndrome and Vascular Dysfunction: Role of Redox-Sensitive PKG-1 and Rho Kinase

“…MR is also expressed in nonepithelial cells, including cardiomyocytes (1), vascular cells (2,3) and macrophages (4,5), and has been implicated in pathological conditions such as heart failure, endothelial dysfunction, hypertension, insulin resistance, and obesity (6)(7)(8)(9)(10). Recently, MR has been identified in adipocytes (11)(12)(13)(14). The (patho)-physiological significance of adipocyte MR is unclear, although experimental and human studies have demonstrated increased expression of adipocyte MR in obesity, metabolic syndrome, and diabetes (6,14,15).…”

“…Recently, MR has been identified in adipocytes (11)(12)(13)(14). The (patho)-physiological significance of adipocyte MR is unclear, although experimental and human studies have demonstrated increased expression of adipocyte MR in obesity, metabolic syndrome, and diabetes (6,14,15). Adipose tissue has long been considered primarily as simple fat storage of triglycerides to regulate several important functions, such as energy balance and thermogenesis, but is now recognized as a metabolically active endocrine/paracrine/autocrine organ that synthesizes, stores, and secretes hormones, vasoactive factors, and proteins, termed adipo(cyto)kines (16,17).…”

“…These mice exhibit features of metabolic syndrome, including weight gain, insulin resistance, and dyslipidemia, with increased activation of prostaglandin D2 synthase (14). Considering the growing evidence that adipose tissue and adipokines influence vascular tone and that the aldosterone/MR system is involved in vascular pathology associated with cardiovascular disease, we questioned whether upregulation of adipocyte MR in mice leads to vascular dysfunction.…”

“…We generated mice with targeted overexpression of human MR (hMR) in adipocytes using the conditional tetracyclineinducible system, as we recently reported (14) and summarized in Supplementary Fig. 1A and B. Double-transgenic adipocyte MROE (Adipo-MROE) mice were obtained by mating two strains: the monotransgenic tetO-hMR mouse and the monotransgenic transactivator aP2-rtTA mouse.…”

“…Quantitative Real-Time PCR Total RNA was extracted from mature adipocytes, EVAT, PVAT, and mesenteric arteries, as previously described (13,14). Real-time PCR was performed on a 7900HT Fast Real-Time PCR machine (Applied Biosystems) using gene-specific primers to quantify the relative abundance with SYBR Green I as the fluorescent molecule.…”