Obesity generates a state of chronic low-grade inflammation systemically and within visceral adipose tissue. This inflammation is a critical link between obesity and the development of metabolic diseases such as type 2 diabetes. As a result, decades of research has focused almost exclusively on understanding how adipose tissue inflammation is induced with nutrient excess. Currently, there is very little is known about how or if adipose tissue inflammation is resolved with the weight loss interventions that reverse obesity. The next generation of scientists poised to answer this and other questions at the interface between metabolism and immunology require a unique set of skills. Towards this end, the purpose of this training proposal is to provide training in obesity and metabolism research to an accomplished pre-doctoral candidate in Immunology with extensive past training in immunity. This training will include didactic, small group, and bench training overseen by a mentorship team of established investigators in immunometabolism research. The scientific training will be carried out by investigating the mechanisms by which adipose tissue leukocytes respond to weight loss interventions. Preliminary studies carried out by the applicant have made the novel observation that inflammatory adipose tissue macrophages are sustained in adipose tissue after diet induced weight loss. This is associated with a reactivation of adipose tissue T cells and appears to differ from pharmacologic weight loss interventions. Three scientific aims will be addressed: 1) To determine the metabolic consequences of maintaining inflammatory activation of adipose tissue leukocytes after weight loss. This will relate the inflammatory changes to adipocyte function and metabolic measures and provide training in nutrient metabolism assessment. 2) To compare and contrast adipose tissue inflammation in pharmacologic and diet- switch models of weight loss. Amlexanox, an inhibitor of stress kinases TANK-binding kinase 1/I?? kinase epsilon, induces weight loss similar to the dietary model developed. Understanding the difference and similarities between leukocyte responses in the two models can identify novel pathways for intervention and synergy between interventions. 3) To evaluate the importance of T cells in the maintenance of pro-inflammatory ATMs with weight loss. The weight loss model performed in T cell deficient mice will evaluate the hypothesis that T cells contribute to ongoing adipose tissue inflammation. At the end of this training period, we hope to have further exposed the mechanisms and cellular processes involved in the maintenance and resolution of obesity-induced inflammation. More importantly, we hope to have significantly advanced the training of a promising pre-doctoral student poised to be a future leader at the interface between metabolism and inflammation.
The chronic inflammation is generated in adipose tissue with obesity that links obesity with metabolic disease such as diabetes. A major gap in our understanding is how this inflammation is shut off in fat with weight loss or other interventions. This project aims to evaluate the mechanisms regulating deactivation of adipose tissue inflammation with dietary and pharmacologic interventions that induce weight loss. Completing this project and its associated training plan will help train an underrepresented minority student with immunology experience in nutrient metabolism.