Cellular and Molecular Mechanisms Underlying the Development of Brown Adipose Tissue

PROJECT SUMMARY: Obesity and its comorbidities pose an ever-increasing challenge to public health despite massive investments in pharmacologic, surgical, and lifestyle-modifying therapeutic strategies. New strategies are needed to alleviate the worsening metabolic health of the national and global populations. One promising strategy is to harness the innate calorie-burning properties of brown adipose tissue (BAT), a metabolic organ specialized for the conversion of chemical energy to heat. Although active BAT is highly correlated with metabolic health in humans, its overall prevalence is low and declines with age and obesity. BAT-targeted therapeutics will thus require the generation of increased BAT mass. Therefore, it is imperative to understand the physiologic development of BAT. BAT derives from the dermomyotome (DM), a multipotent embryonic tissue that also gives rise to skeletal muscle and dermis. The goal of the current proposal is to define the embryonic progenitor cells in the DM-to-BAT lineage and identify the molecular mechanisms controlling the specification and differentiation of brown adipocytes. Preliminary work has identified candidate progenitor cell populations marked by expression of Cdh4 and Dpp4, respectively, and confirmed that these cell populations derive from the DM. The first aim of this proposal will employ adipogenic differentiation assays and lineage tracing to determine whether Cdh4+ and Dpp4+ cells develop into brown adipocytes in vitro and in vivo. In addition to their potential role as progenitor cells, Dpp4+ cells encapsulate developing BAT and express several signaling molecules, including the brown adipogenic factor BMP7, that may regulate BAT development. Preliminary studies show that GATA6, a transcription factor expressed in Dpp4+ cells, is essential for embryonic BAT development. The signaling genes most enriched in Dpp4+ cells are regulated by GATA6 in other developmental contexts, suggesting that GATA6 may promote BAT development by regulating signaling in Dpp4+ cells. Thus, the second aim of this proposal will test the hypothesis that Dpp4+ cells secrete BMP7 and other signaling factors in a GATA6-dependent manner to promote BAT development. Completion of the proposed work will elucidate the developmental trajectory and molecular mechanisms underlying BAT development, uncovering new cellular and molecular targets for BAT-directed therapeutic interventions. Importantly, the fellowship applicant conducting these studies, Ethan Fein, will obtain rigorous research training that is integrated with his clinical training as a student in the Medical Scientist Training Program (MSTP). His training goals will be accomplished through a comprehensive training plan developed by Ethan and his sponsor, Dr. Patrick Seale. Ethan will benefit from the outstanding training environment provided by the Seale lab, the MSTP, and the University of Pennsylvania as a whole. The research training plan outlined in this fellowship application will maximize Ethan's potential to develop into a successful physician-scientist.