ABSTRACT The obesity epidemic contributes to the increased health burden of chronic inflammatory conditions, including insulin resistance, type 2 diabetes mellitus (T2DM), fatty liver, and cardiovascular disease. New strategies for prevention and treatment are crucial to improve the quality of life for people with obesity and T2DM, especially given that behavioral and lifestyle modifications are ineffective alternatives for most of the affected population. Our long-term objective is to identify safe treatments for obesity and T2DM that can restore the normal endocrine functions of insulin-resistant fat cells. Working towards this objective, we found the FDA-approved rheumatoid arthritis drug auranofin generates anti-diabetic effects. We have robust preliminary data showing auranofin accumulation in WAT reduces leptin abundance in the serum and generates whole-body insulin sensitivity in obese wild-type mice. Surprisingly, elevated leptin levels and blunted beta-adrenergic receptor activity achieved by leptin receptor deletion abolished the anti-diabetic effects of auranofin. This application will build upon our preliminary data and test the hypothesis that impacts of auranofin accumulation in WAT restore beta-adrenergic receptor competence to limit leptin production and benefit systemic metabolism in obesity. The overall goal of this application is to explore how auranofin influences insulin sensitivity in preclinical models of obesity with the expectation that its effects require the vital endocrine hormone leptin. To achieve our overall goal and test the central hypothesis of the proposal, we propose three specific aims. First, we will demonstrate how the leptin receptor in WAT influences the metabolic impacts of auranofin. Second, we will establish the serum leptin decrement required for the anti-diabetic effects of auranofin. Lastly, we will determine the functional role of adipocyte-intrinsic beta-adrenergic receptors that govern the energy balance impacts of auranofin. Ultimately, such knowledge will teach us how to leverage the endocrine functions of WAT to treat obesity and its co- morbidities. Completion of this proposal will tell us how to leverage new pathways that generate metabolic benefits in preclinical models of obesity and potentially allow people accessible therapeutic options to manage insulin resistance and T2DM.