0096 : Adipocyte mineralocorticoid receptor activation leads to metabolic syndrome and induction of prostaglandin D2 synthase

Abstract

Metabolic Syndrome (MetS) is a cluster of metabolic risk factors, including visceral obesity and insulin resistance (IR), associated with a higher risk for cardiovascular events. Adipose tissue plays a central role in the obesity- related metabolic abnormalities and it’s known that Mineralocorticoid Receptor (MR) activation affects adipocyte differentiation and function. In particular, MR blockade has shown significant promise in limiting adipocyte dysfunction and MetS in preclinical models. Moreover it has been shown that adipose tissue secretome shows a paracrine effect on vascular system and cardiac function. In our study we showed that MR expression is increased in visceral adipose tissue (VAT) in a preclinical mouse model of MetS and in obese patients. Thus, we generated a double transgenic mouse model with a conditional and inducible overespression of MR in adipose tissue, demonstrating that, even in the absence of high fat diet HFD, increased expression of MR in adipose tissue contributes to MetS development with multiple metabolic abnormalities, including visceral obesity and body weight gain, glucose intolerance and insulin resistance as well as dyslipidemia. Moreover we identified prostaglandin D2 synthase (PTGDS) as a novel MR target gene in adipocytes and AT56, a specific inhibitor of PTGDS enzymatic activity, blunted adipogenic aldosterone effects. Finally, translational studies showed that expression of MR and PTGDS are strongly correlated in adipose tissues from obese patients. In consideration of our results other analyses are necessary to investigate the effect of the MR overexpressing model-specific adipokine profile on cardiac function. Of particular interest will be the study of the crosstalk between the epicardial adipose tissue (EAT) and the adjacent myocardium by using supernatants obtained from MR overexpressing mice EAT incubation to test the paracrine effect of adipokines on cardiac myocytes function.