OR28-1 Role of Mineralocorticoid Receptor in Metabolic Syndrome

Abstract

Rates of obesity and metabolic syndrome (MetS) are at epidemic levels, leading to a rise of individuals at higher risk of developing diabetes and heart disease. Increased visceral adiposity and hyperglycemia are two shared features of MetS and excess glucocorticoids (GCs). GCs are hormones—acting primarily via the glucocorticoid receptor (GR)—commonly prescribed for inflammatory disorders, yet their use is limited due to many detrimental metabolic side effects. Additionally, GCs are used to facilitate adipogenesis in vitro, though our lab has recently shown that GR is not absolutely required for adipogenesis in vitro or in vivo. In addition to GR, GCs also bind the mineralocorticoid receptor (MR), but there are many conflicting studies as to the exact role of MR in adipogenesis. Though metabolic studies using full body MR-/- mice are impractical since these mice die within 10 days of birth due to salt wasting, we do show that MR-/- mice have white and brown adipose depots that are similar to wild-type littermates at 5 postnatal. To define the role of MR in metabolic syndrome in vivo, we created mice with an adipose-specific deletion of MR (FMRKO) by crossing MRflox/flox mice to adiponectin-cre mice. We first induced MetS by treating FMRKO and MRflox/flox control mice with corticosterone (100µg/mL) via drinking water for 4 weeks. After treatment, fat mass was increased in both FMRKO (from 3.4±0.3 to 9.3±0.7g, p<0.0001) and control mice (from 3.5±0.4 to 9.6±1.6g, p<0.0001). Additionally, fasting glucose was elevated in FMRKO (from 128±18 to 235±89mg/dL, p=0.003) and control mice (from 112±13 to 219±39mg/dL, p=0.023); however, there was no difference between groups for fat mass or blood glucose. Separately, we fed mice a high-fat diet (HFD) for 16 weeks. We saw that FMRKO mice had reduced body weight (39.3±4.2 vs 45.2±3.3g, p=0.002), primarily due to a decrease in fat mass (14.8±2.4 vs 19.2±2.3g, p<0.001) relative to control mice. While there was no difference in glucose tolerance between groups, FMRKO mice had significantly decreased plasma insulin (14.5±5.9 vs 6.4±3.3ng/mL, p=0.001). Impressively, FMRKO mice had increased oxygen consumption and energy expenditure compared to control mice. Furthermore, FMRKO had reduced expression of genes involved in adipogenesis and lipogenesis in adipose tissue, relative to control mice. Collectively, these studies provide new insight to the potential value of MR as a therapeutic target in treating conditions associated with MetS. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.