SUMMARY Macrophages are the most abundant inflammatory cell in obese adipose tissue. And it is well established in animal models that the pro-inflammatory cytokines they produce drive systemic metabolic dysfunction including insulin resistance, which is a major cause of morbidity and mortality in overweight individuals. Emerging evidence suggest that this activation program differs from classic macrophage activation in response to bacterial components, therefore offering the potential for targeted therapies to uncouple obesity from disease through the selective inhibition of macrophage function. Discovering the molecular pathways that regulate this unique program of activation are key to both understanding this basic facet of macrophage biology as well as leveraging it to therapeutic advantage. In preliminary data, we have found that the clusters of microRNAs (miRNAs) containing miR-23, miR-24 and miR-27 regulate the production of pro-inflammatory cytokines in culture conditions that model the obese adipose tissue microenvironment. The aims proposed in this grant will determine the function of this cluster of miRNAs in obese adipose tissue macrophages as well as define the network of genes regulated by these miRNAs in macrophages. We will use well-established diet induced obesity mouse models with newly generated miRNA conditional knock out mice as well as state-of-the-art approaches in RNA biology to investigate the unique cellular and molecular mechanisms that regulate these macrophages. Obesity affects nearly 40% of the adult population of the US and increases the risk of diabetes, cardiovascular disease and cancer. Ultimately, strategies including the use of RNA therapeutics to target miRNAs and their gene networks could offer a novel approach to modify macrophage function to control obesity-associated inflammation and mitigate the effects of associated chronic diseases.