A major goal of this laboratory is to understand the molecular mechanisms by which the nuclear receptor peroxisome proliferator-activated receptor ? (PPAR?) regulates metabolism. PPAR? is the master regulator of adipocyte biology and has important metabolic and anti-inflammatory effects in macrophages. It is also the major target of thiazolidinedione (TZD) drugs that have unique abilities to reverse insulin resistance. A major goal of the present proposal is to understand how PPAR? and TZDs function at the nexus of dietary and genetic influences on adipocyte and macrophage biology in obesity and diabetes. Specific Aim 1 is to understand the role of adipose PPAR? in metabolic dysfunction and its treatment by mining the convergence of diet, antidiabetic drugs, and genetics. We will use state-of-the-art genome-wide approaches and mutational analysis to determine the mechanisms of convergence of diet, drugs, and genetics in metabolic disease. Specific Aim 2 is to determine the transcriptional and cellular mechanisms by which PPAR? in adipose macrophages contributes to the antidiabetic effects of TZDs. We will elucidate the PPAR?-dependent effects of TZDs on oxidative metabolism of peritoneal and adipose tissue macrophages (ATMs), and determine whether these effects on ATMs occur in vitro and in vivo. The mechanism of these effects will be determined using genome-wide approaches and mutational analysis. Specific Aim 3 is to delineate genomic modulators of TZD action and PPAR? function in human adipose tissue and macrophages. We will determine individual-specific effects of natural genomic variation on adipocyte TZD responsiveness, and the underlying molecular mechanisms. This approach will also be applied to human macrophages, including ATMs, to determine the extent and importance of natural genetic variation in determining the actions of TZDs and PPAR? in macrophages. Together, using innovative approaches, we will address major questions about the molecular mechanisms underlying gene-environment interactions that are implicated in individual differences in obesity, diabetes, and the response to antidiabetic drugs. Our focus on adipose tissue and macrophages is appropriate given the established importance of these tissues in obesity and diabetes, and the effects of TZDs on these tissues. Our innovative genome-wide and systemic approaches will also provide fundamental insight into the molecular mechanisms underlying tissue-specific and individual-specific effects of transcription factors. Studies of human adipocytes and macrophages will determine the extent of translatability of the mouse findings, and provide insights that will inform strategies for personalized and precision approaches to the treatment of metabolic and inflammatory diseases. This knowledge will thus shed new light on the transcriptional and epigenomic control of adipocyte and macrophage biology and organismal metabolism, with translational relevance including the potential to lead to new and more selective insulin-sensitizing agents to combat the epidemics of obesity and diabetes in modern society.