YY1-mediated transcriptional control of thermogenic-secreted factors in brown fat

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 DESCRIPTION (provided by applicant): YY1-mediated transcriptional control of thermogenic-secreted factors in brown fat Metabolic disorders such as obesity afflict millions of Americans and are a significant economic strain on the national healthcare system. Obesity is the result of an imbalance in caloric consumption and energy expenditure. Increasing energy expenditure by targeting cellular bioenergetics in adipose tissue or muscle may be a promising avenue in treating obesity. However, fundamental questions regarding the cellular mechanisms by which specific tissues regulate whole body energy expenditure must first be addressed. Yin- Yang1 (YY1) is a transcription factor that modulates thermogenesis and oxidative metabolism in highly metabolic tissues through interaction with either peroxisome-proliferator-activated receptor coactivator (PGC)- 1alpha to increase mitochondrial gene expression, or with Polycomb Group (PcG) repressors to suppress gene expression. Our preliminary data show that while brown/beige adipose tissue-specific YY1 knockout mice (YY1-Ucp1KO) exhibit a thermogenic deficiency in brown adipose tissue (BAT), these mice are protected from diet-induced obesity and have increased energy expenditure; this is consistent with increases in Gdf15 and Bmp8b thermogenic-secreted factors. Therefore, these preliminary results prompted us to investigate how YY1 suppresses these secreted factors in BAT as well as identifying and characterizing the involvement of other tissues targeted by BMP8b and GDF15 in mediating whole body energy expenditure. We hypothesize that these secreted factors are directly regulated by YY1 and can act on other metabolic tissues to increase whole body energy expenditure, compensating for thermogenic defects in BAT due to YY1 deficiency. This proposal aims to investigate how YY1 suppresses gene expression of Gdf15 and Bmp8b to promote obesity and to decrease whole body energy expenditure. Aim 1 will elucidate the mechanisms whereby the YY1 transcriptional complex regulates Gdf15 and Bmp8b in BAT. We will examine YY1's interactions with known repressors such as PcGs, as well as investigate epigenetic histone modifications that may result in a decrease in Gdf15 and Bmp8b gene expression. Additionally, we will also investigate YY1 interactions in the presence of physiological stimuli such as, excessive caloric intake and cold-exposure. Aim 2 will identify and characterize the GDF15- and BMP8b-targeted tissues in YY1-Ucp1KO mice with increased energy expenditure that compensate for partial thermogenic deficiencies in BAT. Once we have identified these tissues, we will further investigate gain- and loss-of-function effects of GDF15 and BMP8b both in vitro and in vivo for specific tissue types. The results of this proposal will provide new insights into the molecular mechanisms by which YY1 transcriptional complex in BAT regulates bioenergetics capacities and whole body energy expenditure through controlling secreted factors. These outcomes will open up new possibilities in discovering potential novel therapeutic targets and mechanisms that can ultimately be used to treat obesity and its associated disorders.