Thermogenic chromatin remodeling control and fat tissue communication

生热染色质重塑控制和脂肪组织通讯

• 批准号: 10133056
• 负责人: Pere Puigserver
• 金额: $ 50.39万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10133056
• 关键词: Acetylation; Adipocytes; Adipose tissue; Adult; Age; Biochemical; Bioenergetics; Body Temperature; Body Weight; Body Weight decreased; Body mass index; Brown Fat; Calories; Cardiovascular Diseases; Chromatin Remodeling Factor; Communication; Complex; Consumption; Coupling; Diet; Dietary intake; Ectopic Expression; Energy Intake; Energy Metabolism; Epigenetic Process; Failure; Fatty acid glycerol esters; Funding; GDF15 gene; Gene Expression; Gene Proteins; Genes; Genetic Models; Genetic Transcription; Goals; Grant; Health; Human; Laboratories; Life; Link; Malignant Neoplasms; Mediating; Medical; Metabolic; Metabolic Diseases; Mitochondria; Molecular Analysis; Molecular Target; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity associated disease; Outcome; Outcome Study; Overnutrition; Process; Proteins; Proteome; Regimen; Relapse; Repression; Respiration; Route; Temperature; Therapeutic; Thermogenesis; Tissues; Transcription Repressor; YY1 Transcription Factor; base; chromatin remodeling; diet-induced obesity; dietary; energy balance; exercise program; gene repression; in vivo; loss of function; mouse genetics; novel strategies; novel therapeutic intervention; obesity management; obesity treatment; oxidation; programs; protein complex; response; targeted treatment; transcription factor; uncoupling protein 1; weight maintenance

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.

概括 肥胖是与危害生命并发症（例如心血管）相关的主要健康问题 疾病，2型糖尿病和癌症。肥胖是通过饮食方案进行选择的，可有选择地降低能量 摄入量和/或运动计划的重点是能量消耗。这些疗法的失败很高， 复发率敦促专注于靶向药物的疗法的新策略。人类的最新发现显示 棕色和米色的热功能的激活可以增加能量消耗 靶向控制体温和重量的这些组织中的分子成分。但是， 控制热基因表达和全身能量的组件的调节机制 平衡并不完全理解。转录因子yy1控制着热功能 棕色和米色脂肪通过编码这种代谢和代谢的基因的转录和表观遗传变化 充满活力的程序。我们以前的研究发现，脂肪中缺乏转录因子YY1的小鼠 组织受到强烈保护，免受饮食诱导的肥胖症的影响。从机械上讲，这种保护是由事实引起的 YY1可以抑制激活米色脂肪热活性的棕色脂肪分泌的蛋白质。在这笔赠款中 更新，我们提出的研究将重点放在热脂肪细胞中的两个主要过程上。 （1）定义 通过INO80复合物控制线粒体生物能基因的特定YY1激活函数 表达，（2）定义控制激活的棕色脂肪分泌蛋白的YY1抑制功能 米色脂肪热功能。因为两个调节过程都与能源直接相关 他们对代谢疾病的潜在治疗方法具有很强的意义。主要目标 该应用的是确定转录和表观遗传机制，重点是YY1/INO80 染色质重塑络合物和分泌的蛋白质，呈棕色和米色脂肪的基础 促进能量消耗并预防肥胖的功能。提出了三个不同的目标， 1）YY1/INO80染色质重塑复合物如何转录和表观遗传调节分析 控制棕色脂肪组织中的线粒体/热和分泌蛋白基因表达程序 （特定目标1），2）由YY1/INO80依赖性热介导的代谢和生物能分析 并在棕色和米色脂肪细胞中分泌的基因表达程序（特定目的2）和3）能量和 代谢分析响应于通过YY1/INO80介导的冷和饮食诱导的热发生 转录复合物和GDF15分泌蛋白（特定目标3）。此应用程序的结果将 确定根据响应可调节生热的转录和表观遗传机制 通过YY1/INO80染色质重塑络合物驱动的冷和营养不良。由于肥胖与 无法抵消饮食摄入量增加的能量消耗不足，我们的研究已经 对肥胖治疗的治疗意义。

项目成果

Decreased genetic dosage of hepatic Yin Yang 1 causes diabetic-like symptoms.

• DOI: 10.1210/me.2013-1173
• 发表时间: 2014-01
• 期刊: Molecular endocrinology
• 作者: Francisco Verdeguer;Sharon M. Blättler;John T. Cunningham;J. Hall;H. Chim;P. Puigserver

A sweet way to regulate cellular growth: OGT and mTOR join forces.

调节细胞生长的甜蜜方式：OGT 和 mTOR 联手。

• DOI: 10.1016/j.molcel.2023.07.016
• 发表时间: 2023
• 期刊: Molecular cell
• 影响因子: 16
• 作者: Latorre-Muro,Pedro;Puigserver,Pere
• 通讯作者: Puigserver,Pere

GCN5 acetyltransferase in cellular energetic and metabolic processes.

• DOI: 10.1016/j.bbagrm.2020.194626
• 发表时间: 2021-03
• 期刊: Biochimica et biophysica acta. Gene regulatory mechanisms
• 作者: Mutlu B;Puigserver P
• 通讯作者: Puigserver P

Bromodomain Inhibitors Correct Bioenergetic Deficiency Caused by Mitochondrial Disease Complex I Mutations.

• DOI: 10.1016/j.molcel.2016.08.023
• 发表时间: 2016-10-06
• 期刊: MOLECULAR CELL
• 影响因子: 16
• 作者: Barrow, Joeva J.;Balsa, Eduardo;Verdeguer, Francisco;Tavares, Clint D. J.;Soustek, Meghan S.;Hollingsworth, Louis R.;Jedrychowski, Mark;Vogel, Rutger;Paulo, Joao A.;Smeitink, Jan;Gygi, Steve P.;Doench, John;Root, David E.;Puigserver, Pere
• 通讯作者: Puigserver, Pere

Targeting adaptive cellular responses to mitochondrial bioenergetic deficiencies in human disease.

• DOI: 10.1111/febs.16195
• 发表时间: 2022-11
• 期刊: The FEBS journal
• 作者: Bennett CF;Ronayne CT;Puigserver P
• 通讯作者: Puigserver P