PROJECT SUMMARY/ABSTRACT Excessive adipose tissue expansion causes obesity, a major risk factor for the development of metabolic disease. Three types of fat cells exist -white, brown and beige- involved in maintaining the balance between calories hoarded and those consumed. It has been recently suggested that increasing energy dissipation via the induction of thermogenesis in brown and beige adipocytes could represent a strategy to combat metabolic disease; however, at the present time, our understanding of the key targetable regulators involved in this process is still limited. My laboratory has identified the heat shock factor HSF1 as a novel transcriptional regulator of thermogenesis and has preliminary evidence demonstrating that HSF1 regulates histone demethylases, that obesity is associated with low levels of HSF1 and that ablation of HSF1 in fat leads to metabolic dysfunction. Based on this knowledge, we propose to determine how fat tissue is epigenetically reprogrammed in obese states and identify new molecular mechanisms controlling adipose tissue biology through the analysis of novel upstream regulators and downstream effectors of HSF1 in fat. The results of our studies will identify novel regulatory mechanisms controlling adipose tissue biology and specific epigenetic signatures contradistinctive of obese fat, identify HSF1 is a novel molecular link between extrinsic stimuli and transcriptional and epigenetic re- programming of adipose tissue, and a possible new therapeutic target for the treatment of metabolic dysfunction. To perform the studies outlined we will take advantage of unique fat specific HSF1- and adenosine receptor A2A knock-out mice generated in our laboratory and of techniques and reagents generated over the years and more innovative ones. In Aim 1 will identify novel chromatin signatures in adipose tissues associated with obesity and will assess the role of HSF1 in the epigenetic control of adipose tissue biology and homeostasis; in Aim 2 we will characterize novel regulators of adipocyte biology through the identification of new molecular targets of HSF1 in adipocytes, using state-of-the-art next generation sequencing technologies, in addition to candidate approaches; in Aim 3 we will identify novel pathways regulating innate thermogenesis in fat cells. We expect that the studies outlined will illuminate novel mechanisms that control energy balance in physiological and pathological metabolic states and will define new approaches to increase energy dissipation and combat metabolic disease.

PROJECT NARRATIVE An imbalance between caloric intake and output leads to excessive adipose tissue expansion and obesity, a major risk factor for the development of metabolic disease. Brown and beige adipocytes burn calories and have been considered possible therapeutic targets to fight obesity and metabolic disease also in humans. Here we propose to uncover novel mechanisms that govern adipose tissue function to ultimately devise novel therapeutic approaches to decrease metabolic dysfunction.