Although it is well established that obesity is associated with a state of chronic, low-grade inflammation, which contributes to the metabolic dysregulation of obesity, in many ways we have only begun to scratch the surface of this important area of study. Our work over the last number of years has focused on understanding the contribution of a number of resident liver immune cells to the pathogenesis of the obese liver immunophenotype and associated metabolic abnormalities. Our most recent work (Appendix 1) demonstrated that dendritic cells (DC) are elevated in liver and adipose tissue of obese mice, that depleting or increasing DC alters tissue macrophage and T-cell content, and that mice lacking DC are protected against the development of diet-induced obesity. Questions addressed in the current proposal arise from this work, and will take our focus in a number of novel directions. Thus, the current proposal will test hypotheses, supported by preliminary data, that excessive fatty acid delivery to the liver from adipose tissue is a primary signal initiating the lver immune system response to overnutrition, driven by increased oxidative stress, and that an early event is the recruitment of DC. We propose that DC, once recruited, play a central role in coordinating the liver inflammatory response, specifically by their capacity to activate T-cells an macrophages, possibly at portal associated lymphoid tissue. Furthermore, and again supported by preliminary data, we propose that the reactive oxygen species (ROS) producing enzyme, xanthine oxidoreductase (XOR), plays a critical role in mediating the effects of FFA on liver inflammatory responses in obesity. These hypotheses will be addressed in two specific aims, and will use a number of primary cell culture and mouse models, to which immunological, metabolic, biochemical and molecular analysis will be applied. The overarching goal of our work, of which these projects form an important component, is to obtain an integrated understanding of the mechanisms and functions of immune system alterations in health and disease as they pertain to metabolic regulation.