ORPHAN RECEPTOR COUP-TFII IN ADIPOCYTE DIFFERENTIATION

肥胖症的一个主要公共卫生问题是肥胖症增加了患II型糖尿病的风险 和心血管疾病。为了减少肥胖的流行，我们需要了解潜在的 脂肪形成的机制，以便有效的预防和治疗策略， 来克服这些代谢紊乱。COUP-TFII是核受体的成员 在发育过程中在间充质细胞中高度表达。COUP-TFII消融术 小鼠由于血管生成和心脏发育缺陷导致早期胚胎死亡。期间 在分析COUP-TFII杂合子小鼠表型的过程中，我们注意到突变小鼠 与对照同窝仔相比，它们更瘦，并且它们的脂肪组织量减少。此外，本发明还提供了一种方法， 通过表达UCP-1，腹部白色脂肪组织看起来更像棕色脂肪组织， 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 脂肪样组织，COUP-TFII杂合突变体是更胰岛素敏感和葡萄糖耐受。使用 3 T3 L1细胞培养模型，我们证明COUP-TFII在扩增过程中高度诱导 脂肪细胞分化阶段。3 T3 L1早期COUP-TFII表达的敲低 脂肪细胞分化破坏分化程序并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探索的脂肪细胞调节因子， 分化为了理解COUP-TFII的作用，我们将使用组织特异性和条件性两种方法。 敲除以及体外细胞培养分化系统来剖析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 COUP-TFII在脂肪形成过程中的作用;目的2：研究COUP-TFII调节脂肪形成的机制。 目的3：分析脂肪细胞中COUP-TFII靶基因。我们的研究是 及时，并将揭示COUP-TFII作为脂肪生成调节剂的新信息，并提供 肥胖干预的额外目标。

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.