(limit 30 lines): This application is for a fellowship awarded by the National Institute of Diabetes, Digestive and Kidney Diseases to predoctoral physician-scientist trainees. This applicant is a trainee at the Medical Scientist Training Program at the Perelman School of Medicine at the University of Pennsylvania. This award would provide him with the opportunity to improve his research skills and scientific communication preparing him for a career as an academic physician scientist studying diabetes and obesity pathogenesis. Obesity is a major driver of mortality throughout the world. One approach for treating obesity is to target thermogenic adipose tissue, a metabolic organ that burns energy to perform nonshivering thermogenesis. Harnessing thermogenic adipose fat to increase energy expenditure has great therapeutic potential to treat obesity as increasing thermogenic adipose function prevents diet-induced obesity in a variety of animal models. I have identified Kininogen 2 (KNG2) as a potential brown adipocyte-derived regulator of BAT metabolism. Kininogens are multifunctional secreted proteins that produce the vasodilatory nonapeptide bradykinin (BK) upon enzymatic cleavage. BK acts locally to activate its G-Protein Coupled Receptor, Bradykinin Receptor 2 (BDKRB2). I have determined that Kininogen 2 mRNA is highly expressed in brown adipose tissue and regulated by a key lineage determining factor, Early B Cell Factor 2. Furthermore, I have demonstrated that signaling through BDKRB2 is required for basal and sympathetic-stimulated uncoupled respiration in brown adipocytes. Therefore, this proposal will determine the mechanism by which a novel signaling axis through Kininogen 2 (KNG2) and Bradykinin Receptor 2 (BDKRB2) regulates thermogenic adipose tissue acclimation using in vitro and in vivo metabolic approaches. Understanding how brown fat facilitates acclimation to cold and harnessing brown fat activity to increase energy expenditure have great therapeutic potential to treat obesity. These studies will describe a role for a novel signaling axis in brown adipocyte metabolism with the ultimate goal of informing obesity therapeutic generation.
(limit 2-3 sentences): Obesity and its related conditions drive morbidity and mortality throughout the world. Increasing the activity and amount of thermogenic adipose tissue decreases obesity in humans and rodents; therefore, understanding the mechanisms regulating thermogenic adipose tissue activity are required to improve the translatability of these strategies. The results from the studies in this fellowship will reveal novel mechanisms underlying thermogenic adipose tissue acclimation to cold exposure and hypernutrition, which will have potential to identify new therapeutic targets for the treatment of metabolic syndrome.
