Obesity-induced inflammation is mechanistically linked to insulin resistance and type 2 diabetes. Adipose tissue is a target for both innate and adaptive immune system activation, which forms a unique network for inflammatory responses. Within adipose tissue, immune cells respond to dysregulated obesity-induced adipose tissue expansion and subsequent disruption of adipocyte function. There are many gaps in our knowledge regarding the function of CD4+ T cells in adipose tissue including their mechanism of activation, their cytokine producing capacity, how T cells function in different depots, and the properties of T cells in diabetic humans. The goal of this project is to address some of these gaps while training a pre-doctoral trainee in immunology and metabolism while providing career development instruction necessary for developing an independent academic scientist. The central hypothesis of the proposal is that adipose tissue T (ATT) cells are activated and proliferate in response to adipocyte-derived proteins resulting in the secretion of pro-inflammatory products in a depot specific manner. The premise for this hypothesis is based on the existing literature and preliminary data, which demonstrates a wide range of responses of ATT cells upon stimulation in a novel in vitro activation assay. The research training proposed will address two specific aims: 1) To determine whether endogenous adipose tissue contents contribute to the inflammatory nature of ATT cells. 2) To assess ATT cell activation in response to altered adiposity. The approach will use mouse models of obesity combined with state of the art assessments of activated T cells in adipose tissue. Determining how ATT cells respond in different nutrient environments will elucidate their contribution to disordered metabolic states. In addition, complementary assessments in adipose tissue biopsies from obese patients will inform our murine studies and become a platform for discovery. The training plan will use opportunities provided in the research plan to administer training to the applicant in experimental immunology techniques, assessments of metabolism and obesity in mouse models, applications of translational research to immunometabolism, and build career development skills required for an independent scientific career. Sponsors and advisors with expertise in immunology, metabolism, and human subjects research will oversee the proposed project and training plan to develop a young researcher uniquely trained at the interface between obesity science and immunology.
Chronic low-grade inflammation in adipose tissue is a link between obesity and diabetes. This project will determine how obesity-associated inflammation is modulated by adipose tissue resident T cells. Completing this project and its associated training plan will aid in further developing a pre-doctoral candidate with interdisciplinary training in immunology and metabolism.
