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.

肥胖的一个主要公共健康问题是肥胖会增加患II型糖尿病的风险。 和心血管疾病。为了减少肥胖率，我们需要了解潜在的 脂肪生成的机制，有效的预防和治疗策略可以是 以克服这些新陈代谢障碍。Coup-TFII是核受体的一员 超家族，在发育过程中高表达于间充质细胞。GaP-TFII的烧蚀 由于血管生成和心脏发育的缺陷，小鼠会导致早期胚胎死亡。在.期间 在分析COUP-TFII杂合子小鼠的表型过程中，我们注意到突变小鼠 与对照仔猪相比，它们更瘦，脂肪组织质量减少。此外, 腹部白色脂肪组织通过表达UCP-1，a 棕色脂肪细胞的标志物，对适应性产热很重要。与棕色的增加一致 在脂肪样组织中，COUP-TFII杂合子突变体对胰岛素和葡萄糖耐量更高。vbl.使用 3T3L1细胞培养模型，我们证明了COUP-TFII在扩增过程中被高度诱导 脂肪细胞分化阶段。抑制COUP-TFII在3T3L1早期的表达 脂肪细胞分化会扰乱分化程序，损害甘油三酯的积累。 这些发现表明COUP-TFII可能是一种重要但尚未被发现的脂肪细胞调节因子 差异化。为了理解COUP-TFII的作用，我们将同时使用组织特异性和条件性 通过基因敲除和体外细胞培养分化系统研究COUP-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：确定在体内的作用 COUP-TFII在成脂过程中的作用；目的2：研究COUP-TFII的调控机制 目的3：分析脂肪细胞中COUP-TFII靶基因。我们的研究是 及时并将披露有关COUP-TFII作为脂肪生成调节因子的新信息，以及提供 肥胖干预的额外目标。