Research Projects

Brown and beige adipocytes are densely packed with a high content of mitochondria and are highly thermogenic in nature. Brown fat executes uncoupled respiration through uncoupling protein 1 (UCP1), a mitochondrial-specific protein that generates proton leak in the inner mitochondrial membrane and uncouples ATP synthesis. Uncoupled respiration is the most crucial phenomenon that accounts for the anti-obesity and anti-diabetic properties of brown and beige fat. Previously, we reported that EBF2 (Early B cell factor 2) is a key transcription factor in brown fat development and function. The genetic ablation of this factor reduces mitochondrial function and subsequently affects brown and beige fat formation in mice. However, the molecular mechanism by which EBF2 regulates mitochondrial function, membrane lipid remodeling, dynamics and number is unknown in various physiological conditions, including aging and obesity. Importantly, the role of the other isoform, Early B cell factor 3 (EBF3), is not yet known in adipose tissue and its function. To determine the EBF2 role in mitochondrial function, we employed quantitative lipidomics in mitochondria of wild-type and Ebf2-/- brown adipocytes. Strikingly, our preliminary data support that Myf5Cre-driven loss of Ebf2 causes a drastic change in mitochondrial phospholipids and alters the expression of mitochondrial dynamics marker proteins in neonatal brown fat mitochondria (Fig. 2-3). The lipid-protein composition of mitochondrial membranes is critical for mitochondrial function, integrity and dynamics. Thus, the intriguing question is: How does EBF2 and/or EBF3 maintain the integrity of mitochondrial content, lipid composition, fission-fusion dynamics and mitophagy processes in brown and beige adipogenesis? In this proposal, we intend to examine whether EBF2/3 controls and maintains the integrity of mitochondrial membrane composition and dynamics during aging and diet-induced obesity. Further, we are interested in studying the transcriptional control of EBF2 and EBF3 in reprograming of lipid homeostasis and their gene targets during aging, obesity and cold-induced brown and beige fat formation. Our research group at the Department of Developmental Biology and Genetics is well-integrated with state-of-the-art facilities to execute our proposed objectives in the grant. For this project, my laboratory has also generated brown fat and adipose tissue-specific Ebf2 knockout mice (Ebf2-AKO) and Ebf3flox/flox mice. Together, the facilities in the department and institute and my expertise in the field of metabolic disease and transcriptional regulation of adipogenesis would add another layer of strength to complete this proposal successfully. Objectives: The following objectives will be implemented in both Brown and Beige adipocytes under various metabolic conditions, such as obesity and aging, to establish our research proposal. • Determine the role of EBF2 and EBF3 in the lipid homeostasis of brown and beige fat • Examine the action of EBF2 and EBF3 on mitochondrial dynamics and composition • Study EBF2 and EBF3-mediated transcriptional control on aging and obesity-induced reprograming of adipose tissue