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.
The prevalence of obesity and Type 2 diabetes (diabesity), and attendant metabolic abnormalities including dyslipidemia, insulin resistance, and steatosis has reached near epidemic proportions in western societies. More recently, it has become apparent that the immune system may play an important role in the development of these metabolic abnormalities. Our recent work, along with that of others, has highlighted the importance of dendritic cells (DC) in the immune system response to obesity. The work program in this proposal will focus on understanding the role of DC in the inflammatory response of liver in obesity, the role of adipose tissue derived fatty acids in initiating the inflammatory responses of liver in obesity, and the role of liver oxidative stress in mediating the effects fatty acids. Or work will focus on identification of DC subsets important for liver inflammatory responses, their functions in coordinating the obese immunophenotype of liver, and the mechanisms of their recruitment and actions. 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.
