COBRE Pilot Project for Ryan Temel: Center of Research in Obesity and Cardiovascular Disease

The prevalence of obesity in adults and children has reached an epidemic level in the United States and around the world. Obesity can have significant adverse effects on the development of many diseases including type II diabetes and cardiovascular disease. In general, obesity and associated metabolic disorders appear to stem from multiple abnormalities in adipose tissue function, including the disruption of lipid homeostasis and activation of inflammatory signaling. This proposal will examine the novel hypothesis that scavenger receptor BI (SR-BI) plays an important and previously unrecognized role in modulating stress signaling in adipocytes and thereby inflammation in adipose tissue. SR-BI is an HDL receptor that plays a key role in plasma lipid metabolism by internalizing HDL cholesteryl ester into the liver and steroidogenic tissues. Other functions have also been described for SR-BI, including the efflux of cellular cholesterol and dampening of inflammatory cytokine production in macrophages. Despite being expressed in adipocytes, the function of SR-BI in these cells has received little attention and remains unclear. Recent studies by our group have shown that SR-BI in adipocytes, as in macrophages, exerts an anti-inflammatory effect by inhibiting the production of pro-inflammatory cytokines. Conversely, inactivation of SR-BI in adipocytes results in increased triglyceride and cholesterol accumulation. These results are in line with the findings that, compared to wild type control mice, SR-BI-/- mice on a high fat diet exhibit increased fat mass characterized by elevated proinflammatory cytokines and adipose tissue inflammation. SR-BI-/- mice also displayed signs of metabolic disorder with increased circulating free fatty acids levels, glucose intolerance and attenuated insulin signaling in adipose tissue. On basis of these findings, SR-BI is likely to limit obesity and associated metabolic disorders by curbing in adipose tissue lipid accumulation and inflammation. Thus, in the current pilot study, we are aiming to evaluate the impact of adipocyte-specific SR-BI expression on diet induced obesity and insulin sensitivity using SR-BI-/- mice. Findings obtained from the proposed study will provide crucial guidance for the future mechanistic studies on SR-BI function in metabolic disorders.