ABSTRACT Chronic dietary energy stress on white adipose tissue (WAT) promotes fat deposition in peripheral tissues, which accelerates insulin resistance and type 2 diabetes mellitus (T2DM). Restoring the capacity of WAT to safely sequester excess energy promotes insulin sensitivity in the face of diet-induced obesity. To this end, we discovered that the microRNA miR-30a exhibits reduced expression in subcutaneous fat from diabetic mice and humans compared to normal controls. Our preliminary studies establish that miR-30a confers upon WAT the ability to withstand the pressure of high fat diet and prevent the co-morbidities of obesity. These changes result in improved whole-body insulin sensitivity coupled with muted WAT inflammation and reduced hepatic steatosis. The effect of miR-30a on WAT function coincides with complete blockade of STAT1 signaling, which is a key transducer of obesity-linked inflammatory cytokines. These exciting studies support the hypothesis that systemic insulin sensitivity is preserved by miR-30a repression of STAT1-mediated inflammation in adipocytes. Intriguingly, miR-30a confers beneficial effects on glucose and lipid homeostasis without reducing body weight. The goal of this proposal is to critically test our hypothesis by challenging our genetic mouse models of miR-30a and STAT1 expression with diet-induced obesity. In Aim 1, we will define the basis underpinning the metabolic effects of miR-30a transgenic expression in WAT. Aim 2 will evaluate the role of the inflammatory transcription factor STAT1 in mediating the metabolic effects of miR-30a expression in subcutaneous WAT. Lastly, Aim 3 will establish the mechanisms governing the transcriptional regulation of miR-30a. Our investigation of the basis by which miR-30a controls WAT function is significant because it will expand our understanding of mechanisms that connect obesity with T2DM. At the completion of our studies, we will have identified mechanisms that might be exploited in therapies to manage insulin resistance and T2DM. PUBLIC HEALTH RELEVANCE: Insulin resistance and T2DM are chronic health problems in the United States. Mechanisms that improve insulin sensitivity by restoring proper fat storage mechanisms represent new paradigms for clinical management of obesity.