Obesity is a leading cause of chronic illness and premature death in the U.S. A promising avenue to reduce obesity and diabetes is through increasing the amount and/or function of energy-dissipating fat cells, called brown and beige adipocytes. Conversely, reduced brown/beige fat activity may predispose some people to type 2 diabetes and obesity. It is thus critical to study how these cell types develop and function. Brown and beige fat cells in adult tissues arise from committed precursor cells called preadipocytes. However, the molecular pathways that regulate preadipocyte commitment or identity are unknown. In this project, we will determine the function of Early B Cell Factor-2 (Ebf2), a transcription factor, in brown fat-lineage commitment and evaluate whether activation of Ebf2 in fat tissue protects animals against obesity and metabolic disease. Brown fat, skeletal muscle, dermis and some white fat cells originate from multipotent mesodermal structures in the embryo called somites. Ebf2 is required for brown and beige fat development and its expression identifies committed brown fat preadipocytes in somites, days before any sign of brown fat differentiation. We hypothesize that Ebf2 expression commits multipotent stem cells to a brown fat-specific fate in somites. To investigate this, we will determine if expression of Ebf2 in somit- derived stem cells converts them into brown preadipocytes and assess whether loss of Ebf2 or certain of its downstream target genes in preadipocytes activates alternative cell fates. Lineage tracing will be used to assess the fate of Ebf2-expressing cells in vivo. Ebf2 turns on a complete brown fat-specific program in adipocytes, but its mechanism of action or physiological effects have not been clarified. We hypothesize that Ebf2 binds to brown fat-specific genes in preadipocytes and makes the chromatin at these sites competent for the binding of other transcriptional activators in adipocytes. To test this, we will analyze the binding of Ebf2 and other key factors, Ppar? and c/EBP?, during the differentiation of wildtype and Ebf2-deficient preadipocytes. Given that Ebf2 expression strongly promotes brown and beige fat differentiation, we hypothesize that activation of Ebf2 in adipose tissue suppresses metabolic disease. To test this, we will analyze the systemic metabolism of mice that ectopically express Ebf2 in adipose tissue and develop a mouse model to investigate whether Ebf2 can acutely induce WAT browning in adults. Taken together, these studies will provide critical insights into how stem cells undergo brown fat lineage commitment. Understanding how Ebf2 functions in brown/beige fat commitment will be crucial for designing approaches to increase brown/beige fat mass for therapeutic effect.

Public Health Relevance

Obesity and its close link to type 2 diabetes, heart disease and many cancers is an enormous public health problem in the U.S. A promising therapeutic avenue to reduce obesity and diabetes is through enhancing the activity of energy-dissipating fat cells, called brown and beige adipocytes. Our goal is to identify the molecules and pathways that control the development of brown and beige fat cells. Early B Cell Factor-2 (Ebf2) is a critical transcriptional regulator of brown and beige adipocyte development and a selective marker of brown preadipocytes. Here, we will elucidate the mechanisms by which Ebf2 drives brown preadipocyte specification and examine whether activation of Ebf2 in adipocytes suppresses obesity and insulin resistance in mice. By studying the natural mechanisms that control beige and brown fat, our studies will reveal novel avenues to expand brown and/or beige fat mass.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
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Haft, Carol R
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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