Thermogenic chromatin remodeling control and fat tissue communication

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Summary Obesity is a current major health problem associated with life threatening complications such as cardiovascular disease, type 2 diabetes and cancer. Obesity is managed with dietary regimens that selectively reduce energy intake and/or exercise programs focused on energy expenditure. These treatments have high failure and relapse rates urging new strategies focused on drug-targeted therapies. Recent findings in humans showing that activation of brown and beige thermogenic function can increase energy expenditure open a new route to target the molecular components in these tissues that control body temperature and weight. However, the regulatory mechanisms of the components that control thermogenic gene expression and whole body energy balance are not completely understood. The transcription factor YY1 controls the thermogenic function in brown and beige fat through transcriptional and epigenetic changes in genes encoding for this metabolic and energetic program. Our previous studies found that mice deficient in the transcription factor YY1 in adipose tissue are strongly protected against diet-induced obesity. Mechanistically, this protection is caused by the fact that YY1 can repress brown fat secreted proteins that activate beige fat thermogenic activity. In this grant renewal, we propose studies that will focus on two main processes in thermogenic adipocytes. (1) Define the specific YY1 activation function through the INO80 complex that controls mitochondrial bioenergetic gene expression, and (2) define the YY1 repression function that controls brown fat secreted proteins that activate beige adipose thermogenic function. Because both regulatory processes are directly linked to energy expenditure they have strong significance towards potential treatments for metabolic diseases. The major goal of this application is to identify the transcriptional and epigenetic mechanisms, focusing on the YY1/INO80 chromatin remodeling complex and secreted proteins, underlying the brown and beige adipose thermogenic function which promotes energy expenditure and protects against obesity. Three different aims are proposed, 1) Transcriptional and epigenetic regulatory analysis of how the YY1/INO80 chromatin remodeling complex controls mitochondrial/thermogenic and secreted proteins gene expression programs in brown adipose tissue (Specific Aim 1), 2) Metabolic and bioenergetic analysis mediated by the YY1/INO80-dependent thermogenic and secreted gene expression programs in brown and beige adipose cells (Specific Aim 2) and, 3) Energy and metabolic analysis in response to cold- and diet-induced thermogenesis mediated through the YY1/INO80 transcriptional complex and GDF15 secreted protein (Specific Aim 3). The outcomes from this application will identify the transcriptional and epigenetic mechanisms that control adjustable thermogenesis in response to cold and overnutrition driven through the YY1/INO80 chromatin remodeling complex. Since obesity is linked to insufficient energy expenditure that is unable to counteract increased dietary intake, our studies have therapeutic implications for obesity treatment.