Thermogenic chromatin remodeling control and fat tissue communication

摘要 肥胖是目前一个主要的健康问题，与威胁生命的并发症有关，如心血管并发症 疾病、2型糖尿病和癌症。肥胖是通过有选择地减少能量的饮食方案来控制的 摄取和/或锻炼计划侧重于能量消耗。这些治疗方法的失败率很高， 复发率促使新的策略专注于药物靶向治疗。在人类身上的最新发现表明 棕色和米色生热功能的激活可以增加能量消耗，为 瞄准这些组织中控制体温和体重的分子成分。然而， 控制生热基因表达和全身能量的成分的调节机制 平衡还没有完全被理解。转录因子YY1控制着体内的生热功能 棕色和米色脂肪通过转录和表观遗传基因的变化编码这种代谢和 充满活力的节目。我们先前的研究发现，脂肪中转录因子YY1缺乏的小鼠 组织受到强有力的保护，不会因饮食导致肥胖。从机制上讲，这种保护是由以下事实引起的 YY1可以抑制棕色脂肪分泌的蛋白质，这些蛋白质激活了米色脂肪的生热活性。在这笔赠款中 更新，我们建议研究将集中在生热脂肪细胞的两个主要过程。(1)界定 控制线粒体生物能基因的INO80复合体对YY1的特异性激活作用 表达，以及(2)定义YY1抑制功能，该功能控制棕色脂肪分泌的蛋白激活 米色脂肪生热功能。因为这两个监管过程都与能源直接相关 这些支出对代谢性疾病的潜在治疗具有很强的意义。主要目标是 这一应用的目的是识别转录和表观遗传机制，重点是YY1/INO80 染色质重塑复合体和分泌蛋白，潜在的棕色和米色脂肪生热 促进能量消耗和预防肥胖的功能。提出了三个不同的目标， 1)YY1/INO80染色质重塑复合体的转录和表观遗传学调控分析 控制棕色脂肪组织中线粒体/产热和分泌蛋白的基因表达程序 (特定目标1)，2)YY1/INO80依赖的产热基因介导的代谢和生物能量分析 和在棕色和米色脂肪细胞中分泌的基因表达程序(特定目标2)和，3)能量和 YY1/INO80介导的寒冷和饮食诱导的产热反应的代谢分析 转录复合体和GDF15分泌蛋白(特异靶3)。此应用程序的结果将 确定控制可调节产热的转录和表观遗传机制以响应 寒冷和营养过剩通过YY1/INO80染色质重塑复合体驱动。因为肥胖与 我们的研究发现，能量消耗不足，无法抵消增加的饮食摄入量 肥胖症治疗的治疗意义。

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.