Engineering Functional Brown Fat with Anti-Obesity Potential

Dana-Farber Cancer Inst, Boston MA

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Abstract

DESCRIPTION (provided by applicant): Obesity is a major risk factor for metabolic disorders such as type-2 diabetes and cardiovascular disease. Obesity results from disturbed energy balance, where energy intake (i.e. feeding) chronically exceeds total energy expenditure. Due to its remarkable oxidative capacity to dissipate excess chemical energy, brown fat activity is tightly linked to the development of obesity and metabolic disorders. Since recent studies clearly demonstrated the existence of significant deposits of active brown adipose tissue (BAT) in adult humans, altering the amount and activity of BAT could provide a novel therapeutic intervention to counteract obesity and metabolic syndrome. We have recently identified a zinc finger protein, PRDM16, as a dominant molecular switch in the fate of brown fat cells via induction of a "brown fat program" in white pre-adipocytes and myf5-positive myoblastic precursors. Most recently, we found that PRDM16 forms a transcriptional complex with the active form of C/EBP-( (LAP), serving as the critical molecular unit that controls the cell fate switch from myoblastic precursors to brown fat cells. Significantly, ectopic expression of these two factors;PRDM16 and C/EBP-( is sufficient to reconstitute a fully functional brown fat program in na[unreadable]ve fibroblastic cells, including skin fibroblasts in vitro and in vivo. This proposal aims to investigate the function and molecular basis of engineered brown fat cells induced by PRDM16 and C/EBP-(. As a main focus of the first phase (K99), we will utilize transplantation of engineered brown fat cells to critically assess their impact on whole body energy expenditure and their anti-obesity potential (Aim1). In the second phase (R00), we will examine the molecular basis by which the PRDM16- C/EBP-( transcriptional complex reprograms a cell fate into brown fat (Aim2). We will also dissect the cAMP signaling pathways to further improve the function of engineered brown fat (Aim3). Together, these studies will uncover the therapeutic potential of engineered brown fat cells for the treatment of obesity and metabolic disorders, and also will open my future research avenue as an independent investigator. PUBLIC HEALTH RELEVANCE: A worldwide epidemic of obesity is now a formidable public health issue, since obesity is a major risk factor for many diseases, including type 2 diabetes, cardiovascular disease, stroke, hypertension, and many cancers. Because adult humans indeed have substantial amounts of functioning brown adipose tissue (BAT) that can counteract obesity by raising energy expenditure, understanding and modulating this pathway may provide new opportunities for the development of novel classes of therapeutics for metabolic diseases like obesity and type 2 diabetes.