Obesity is among the most significant and preventable risk factors for developing osteoarthritis (OA). Efforts to identify the causes of this risk have traditionally focused on obesity-induced trigĀgers of joint stress, such as mechanical and inflammatory factors. Indeed, our previous work has shown that leptin is a key mediator of the link between adiposity and OA. However, we know little about how obesity impairs chondrocyte cellular defense mechanisms resulting in inappropriate or insufficient responses to joint stresses. Recent studies indicate an unexpected role for chondrocyte lipid metabolism in regulating cartilage development and adult tissue remodeling using genetically modified mouse models. We are testing the hypothesis that a high fat diet increases chondrocyte lipid metabolism, resulting in increased acetyl-CoA production and mitochondrial acetylation with increasing age. We are utilizing transcriptomic, proteomic, and metabolomic methods to characterize obesity-related changes in chondrocyte metabolism in vivo.