Transcriptional regulation of beige adipocytes

米色脂肪细胞的转录调控

• 批准号: 8772559
• 负责人: Claudio J Villanueva
• 金额: $ 7.45万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8772559
• 关键词: Adipocytes; Adipose tissue; Adopted; Adult; Appearance; Award; Binding; Biological Testing; Body Temperature; Brown Fat; Burn injury; Calories; Cells; Characteristics; Chronic Disease; Complement; Complex; Consumption; Data; Diabetes Mellitus; Diet; Elements; Energy Intake; Energy Metabolism; Engineering; Equilibrium; Exhibits; Expenditure; Exposure to; Fatty acid glycerol esters; Gene Expression; Genes; Goals; Heating; Immunohistochemistry; In Vitro; Intake; Intervention; Lead; Leukocytes; Link; Lipids; Maps; Measures; Mediating; Metabolic Diseases; Mitochondria; Molecular; Molecular Target; Mus; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathogenesis; Pathway interactions; Peripheral; Peroxisome Proliferator-Activated Receptors; Phenotype; Play; Point Mutation; Proteins; Public Health; Relative (related person); Research; Resistance; Risk; Role; Testing; Thermogenesis; Time; Tissues; Transcript; Transcriptional Regulation; Transgenic Mice; Triglycerides; base; domain mapping; energy balance; in vivo; insight; loss of function; mouse model; new therapeutic target; novel therapeutics; overexpression; oxidation; programs; promoter; public health relevance; research study; response; selective expression; subcutaneous; treatment strategy; yeast two hybrid system

DESCRIPTION (provided by applicant): There is a gap in our understanding of how the white, brown, and beige adipocyte subtypes are programmed to adopt their distinct phenotypic characteristics of storing or burning energy. The imbalance between energy intake and expenditure can lead to obesity and metabolic disorders such as type 2 diabetes. White adipocytes store and mobilize energy for peripheral tissue consumption, while brown adipocytes store and burn energy during cold exposure to generate heat. Beige adipocytes behave like brown adipocytes, but appear in white adipose tissue with long-term cold exposure. Our long-term objective is to better understand how adipocyte precursors are programed to adopt these distinct phenotypic characteristics. Ultimately our goal is to shift the energy balance from storage to expenditure. To this end we have made significant progress in completing our studies described in the KO1 award where we have determined that TLE3 and Prdm16 drive opposing transcriptional programs to stimulate white or brown fat gene expression, respectively. In this RO3 application, we will extend our findings from the KO1 award to gain a molecular understanding of how TLE3 and Prdm16 counter each other's actions. Our hypothesis is that TLE3 directly interacts with Prdm16 to form a mutually neutralized coactivator complex to regulate energy storage or expenditure. Where a bound TLE3-Prdm16 complex is inactive, and unbound TLE3 or Prdm16 are free to interact with PPAR¿ to stimulate energy storage or energy expenditure, respectively. We expect that this interaction will be most important in beige adipocytes where TLE3 and Prdm16 expression is high. Guided by strong preliminary data, this hypothesis will be tested in Aim1 where we will determine the functional significance of the TLE3-Prdm16 interaction, and in Aim2 where we will determine whether TLE3 blocks the appearance of beige adipocytes. Under Aim1, we've engineered several TLE3 and Prdm16 deletions to map the domains that mediate the TLE3-Prdm16 interaction and have developed a yeast-two-hybrid system to identify point mutations that will allow us to test the biological significance of the TLE3-Prdm16 interaction. Under Aim2, we will utilize our unique gain and loss of function mouse models to test whether TLE3 blocks the cold-induced appearance of beige cells in subcutaneous adipose tissue. Understanding the transcriptional mechanisms that distinguish between the adipocyte subtypes will be key to identifying novel therapeutic targets to program cells to adopt the favorable brown/beige adipocyte phenotype to treat obesity.

描述（由适用提供）：我们对如何对白色，棕色和米色脂肪细胞亚型进行编程以采用其独特的储存或燃烧能量的表型特征存在差距。能量摄入和支出之间的不平衡会导致肥胖症和代谢性疾病，例如2型糖尿病。白色脂肪细胞存储并动员能量以进行周围组织消耗，而棕色脂肪细胞在冷暴露期间储存并燃烧能量以产生热量。米色脂肪细胞的行为就像棕色的脂肪细胞，但出现在白色脂肪组织中，长期感冒暴露。我们的长期目标是更好地了解如何对脂肪细胞前体进行编程以采用这些独特的表型特征。最终，我们的目标是将能源平衡从存储转移到支出。为此，我们在完成KO1奖中描述的研究方面取得了重大进展，我们确定TLE3和PRDM16分别推动相反的转录程序以刺激白色或棕色脂肪基因表达。在此RO3应用程序中，我们将从KO1奖中将我们的发现扩展到对TLE3和PRDM16如何对抗对方的行为的分子理解。我们的假设是TLE3直接与PRDM16相互作用，形成相互中和的共激活因子复合物以调节能量储能或支出。如果绑定的TLE3-PRDM16复合物是无活跃的，而Unbound Tle3或PRDM16则可以自由与PPAR相互作用，以刺激能量存储或能量消耗。我们希望这种相互作用在TLE3和PRDM16表达高的米色脂肪细胞中最重要。在强有力的初步数据的指导下，该假设将在AIM1中进行检验，在AIM1中，我们将确定TLE3-PRDM16相互作用的功能意义，在AIM2中，我们将确定TLE3是否会阻止米色脂肪细胞的出现。在AIM1下，我们已经设计了几个TLE3和PRDM16删除，以绘制介导TLE3-PRDM16相互作用的域，并开发了酵母 - 两者杂交系统，以识别点突变，以使我们能够测试TLE3-PRDM16相互作用的生物学。在AIM2下，我们将利用我们的独特增益和功能小鼠模型的损失来测试TLE3是否阻止了皮下脂肪组织中米色细胞的冷诱导外观。了解区分脂肪细胞亚型的转录机制将是识别针对程序细胞的新型治疗靶标，以采用有利的棕色/米色脂肪细胞表型来治疗肥胖。