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（由申请人提供）：我们对白色、棕色和米色脂肪细胞亚型如何被编程以采用其储存或燃烧能量的独特表型特征的理解存在差距。能量摄入和支出之间的不平衡会导致肥胖和代谢紊乱，例如2型糖尿病。白色脂肪细胞储存和调动能量以供周围组织消耗，而棕色脂肪细胞在冷暴露期间储存和燃烧能量以产生热量。米色脂肪细胞的行为与棕色脂肪细胞相似，但长期暴露在寒冷环境下会出现在白色脂肪组织中。我们的长期目标是更好地了解脂肪细胞前体细胞如何被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储存转向支出。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 驱动相反的转录程序，分别刺激白色或棕色脂肪基因表达。在此 RO3 应用中，我们将扩展 KO1 奖项的发现，以从分子角度了解 TLE3 和 Prdm16 如何对抗彼此的行为。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复合物来调节能量储存或消耗。其中结合的 TLE3-Prdm16 复合物无活性，而未结合的 TLE3 或 Prdm16 可以自由地与 PPAR¿ 相互作用，分别刺激能量储存或能量消耗。我们预计这种相互作用在 TLE3 和 Prdm16 表达较高的米色脂肪细胞中最为重要。在强有力的初步数据的指导下，这一假设将在 Aim1 中进行测试，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，我们设计了几个 TLE3 和 Prdm16 缺失，以绘制介导 TLE3-Prdm16 相互作用的结构域，并开发了一种酵母双杂交系统来识别点突变，这将使我们能够测试 TLE3-Prdm16 相互作用的生物学意义。在 Aim2 项目下，我们将利用我们独特的功能获得和丧失小鼠模型来测试 TLE3 是否能阻止寒冷诱导的皮下脂肪组织中米色细胞的出现。了解区分脂肪细胞亚型的转录机制将是确定新的治疗靶点的关键，以编程细胞采用有利的棕色/米色脂肪细胞表型来治疗肥胖。