ORPHAN RECEPTOR COUP-TFII IN ADIPOCYTE DIFFERENTIATION

脂肪细胞分化中的孤儿受体突变-TFII

• 批准号: 7215497
• 负责人: SOPHIA Y. TSAI
• 金额: $ 24万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7215497
• 关键词: adipocytes; bioenergetics; biological signal transduction; cell differentiation; cell growth regulation; gene expression profiling; gene induction /repression; gene targeting; genetically modified animals; glucose metabolism; hormone regulation /control mechanism; insulin sensitivity /resistance; laboratory mouse; microarray technology; nuclear receptors; obesity; tissue /cell culture

A major public health issue in obesity is that obesity enhances the risk of developing type II diabetes and cardiovascular diseases. To reduce the prevalence of obesity, we need to understand the underlying mechanism of adipogenesis such that effective preventive and treatment strategies could be implemented to overcome these metabolic disorders. COUP-TFII is a member of the nuclear receptor superfamily and is highly expressed in mesenchymal cells during development. Ablation of COUP-TFII in mice results in early embryonic lethality due to defects in angiogenesis and heart development. During the course of analyzing the phenotypes of COUP-TFII heterozygous mice, we noted that the mutant mice are leaner and their adipose tissue mass is reduced in comparison to the control littermates. In addition, the abdominal white adipose tissues appear more like brown adipose tissues by expressing UCP-1, a marker of brown adipocytes important for adaptive thermogenesis. Consistent with the increase in brown fat-like tissues, the COUP-TFII heterozygous mutant is more insulin sensitive and glucose tolerant. Using 3T3L1cell culture models, we demonstrated that COUP-TFII is highly induced during the expansion phase of adipocyte differentiation. Knockdown of COUP-TFII expression during the early phase of 3T3L1 adipocyte differentiation disrupts the differentiation program and impairs the accumulation of triglycerides. These findings suggest that COUP-TFII is likely an important but yet unexplored regulator of adipocyte differentiation. To understand the role of COUP-TFII, we will use both tissue specific and conditional knockout as well as in vitro cell culture differentiation system to dissect COUP-TFII's role in adipogenesis. To accomplish these goals, three Specific Aims are proposed: Aim 1: Determine the in vivo role of COUP-TFII during adipogenesis; Aim 2: Investigate the mechanism by which COUP-TFII regulates adipocyte differentiation; Aim 3: Analyze COUP-TFII target genes in adipocytes. Our studies are timely and will reveal new information on COUP-TFII as a regulator of adipogenesis as well as provide additional targets for obesity intervention.

肥胖症中的一个主要公共卫生问题是肥胖增强了患II型糖尿病的风险 和心血管疾病。为了降低肥胖症的患病率，我们需要了解基础 脂肪形成的机制使有效的预防和治疗策略可能是 实施以克服这些代谢障碍。 COUP-TFII是核受体的成员 超家族在发育过程中在间充质细胞中高度表达。消融政府-TFII 小鼠由于血管生成和心脏发育缺陷而导致早期的胚胎致死性。期间 分析政变杂合小鼠的表型的过程，我们注意到突变小鼠 与对照同窝仔相比，更瘦，其脂肪组织质量减少了。此外， 腹部白脂肪组织看起来更像是棕色脂肪组织，通过表达UCP-1，A 棕色脂肪细胞的标记对于自适应生热重要。与棕色的增加一致 脂肪组织，政变-TFII杂合突变体更胰岛素敏感和葡萄糖耐受性。使用 3T3L1细胞培养模型，我们证明了政变在扩展过程中是高度诱导的 脂肪细胞分化的阶段。在3T3L1的早期期间敲低政变-TFII表达 脂肪细胞分化破坏了分化程序并损害甘油三酸酯的积累。 这些发现表明，政府-TFII可能是脂肪细胞的重要但未开发的调节剂 分化。为了了解政变-TFII的作用，我们将同时使用特定于组织和条件 敲除以及体外细胞培养分化系统，以剖析政变TFII在脂肪形成中的作用。 为了实现这些目标，提出了三个具体目标：目标1：确定体内角色 成脂情况期间的政变-TFII；目标2：调查政变调节的机制 脂肪细胞分化； AIM 3：分析脂肪细胞中的政变-TFII目标基因。我们的研究是 及时，并将揭示有关coup-tfii的新信息，作为成生的调节剂，并提供 肥胖干预的其他目标。