Abstract P071: Mineralocorticoid Receptor Overexpression in Adipose Tissue Leads to Metabolic Syndrome and Induction of Prostaglandin D2 Synthase PTGDS and lipocalin-2 NGAL

Abstract

Objectives: Metabolic Syndrome (MetS) is a cluster of metabolic risk factors associated with a higher risk for cardiovascular events. Adipose tissue (AT) plays a central role in the obesity-related metabolic abnormalities and it’s known that Mineralocorticoid Receptor (MR) activation affects adipocyte differentiation and function. The purposes of this study were to evaluate the molecular and metabolic consequences of adipocyte-targeted increase in MR expression in mice. Results: In our study we showed that MR expression is increased in visceral adipose tissue (VAT) in a preclinical mouse model of MetS. Thus, we generated a double transgenic mouse model with a conditional and inducible overexpression of MR in AT (Adipo-MORE), demonstrating that increased expression of MR in AT contributes to MetS development with multiple metabolic abnormalities, including visceral obesity (VAT mass, control-MR 5.0±0.6 adipo-MORE 10.4±1.8, p<0.05), insulin resistance (HOMA index, control-MR 8.9±0.8 adipo-MORE 14.5±2.2, p<0.05) as well as dyslipidemia (total cholesterol, mg/dL control-MR 86.0±6.0 adipo-MR 109±6, p<0.05). We also identified prostaglandin D2 synthase (PTGDS) as a novel mediator of adipogenic effects of MR activation in adipocytes. Since adipokines play pivotal roles in the regulation of insulin sensitivity in obesity, we also focused on the role of lipocalin-2 NGAL, recently identified in our laboratory as a target of aldosterone action in cardiovascular system, as new adipocyte MR target. It’s known that NGALKO mice fed a high fat diet are protected from obesity-induced cardiovascular dysfunctions. In our model we observed an increase of NGAL mRNA levels (3 fold increase, p<0.05) in VAT. Moreover, NGAL was induced (2-8 fold increase, p<0.05) in primary cultures of adipocytes differentiated ex vivo from adipo-MORE mice in presence of aldosterone stimulation compared to controls. Conclusions: We demonstrated that PTGDS is a novel direct MR target in rodent adipocytes mediating adipogenic effects of MR activation. We also found that NGAL is induced in presence of MR overexpression in adipocytes in vivo and ex vivo. In consideration of our results, other analyses are necessary to better understand the role of NGAL as adipocyte MR target.