Role of Beta-Catenin Antagonist Chibby in Adipogenesis

肥胖是美国和其他西方国家的一个主要健康问题， 糖尿病、心血管疾病和几种癌症。相反，脂肪萎缩，缺乏脂肪 组织，也与糖尿病和各种代谢异常有关。因此，理解 调节脂肪细胞分化的细胞和分子基础是发展全面的 预防和治疗这些疾病的治疗策略。典型的Wnt/B-catenin 已显示一种途径抑制脂肪形成，同时通过以下途径维持分裂前脂肪状态： 过表达研究。然而，其生理重要性仍有待阐明。我们报告一个 一种新的B-连环蛋白相关拮抗剂，命名为Chibby（Cby）。Cby是一种保守的核蛋白 在整个进化过程中。我们发现，Cby与B-连环蛋白的C-末端活化结构域相互作用， 通过与Lef-1竞争抑制B-连环蛋白介导的转录激活。我们进一步表明 Cby功能的丧失导致果蝇中该途径的过度激活。为了深入了解 Cby在脊椎动物发育过程中以及在人类疾病中的功能，我们已经创建了Cby-null (Cby-/-）小鼠。出乎意料的是，这些小鼠表现出减少的肥胖。使用培养的3 T3-L1前脂肪细胞，我们 发现Cby蛋白水平在脂肪形成过程中增加。此外，Cby的异位表达导致 相反，Cby RNAi几乎完全阻断了3 T3-L1的脂肪形成。 细胞这些初步数据有力地证明Cby是一种重要的促脂肪形成因子。长期 本申请的目的是阐明Cby在脂肪组织发育中的作用。我们建议分析 Cby-/-小鼠的脂肪组织，研究Cby-/-小鼠胚胎成纤维细胞在 体外培养，前脂肪细胞和多能间充质干细胞的体外培养。我们的研究提供 希望阻断Cby活性可能是治疗肥胖及其相关疾病的有效方法。

Obesity is a major health issue in the United States and other Western countries, increasing the risk of diabetes, cardiovascular diseases and several types of cancers. In contrast, lipoatrophy, the lack of adipose tissue, is also associated with diabetes and various metabolic abnormalities. Thus, understanding the cellular and molecular basis that regulates adipocyte differentiation is necessary to develop comprehensive therapeutic strategies for the prevention and treatment of these disorders. The canonical Wnt/B-catenin pathway has been shown to inhibit adipogenesis while maintaining a dividing preadipoctye state through overexpression studies. However, its physiological importance remains to be elucidated. We reported a novel B-catenin-associated antagonist, termed Chibby (Cby). Cby is a nuclear protein that is conserved throughout evolution. We showed that Cby interacts with the C-terminal activation domain of B-catenin and represses B-catenin-mediated transcriptional activation by competing with Lef-1. We further demonstrated that loss of Cby function leads to hyperactivation of the pathway in Drosophila. To gain insights into the function of Cby during vertebrate development as well as in human disease, we have created Cby-null (Cby-/-) mice. Unexpectedly, these mice exhibit reduced adiposity. Using cultured 3T3-L1 preadipocytes, we found that Cby protein levels increase during adipogenesis. Furthermore, ectopic expression of Cby causes spontaneous differentiation, and conversely, Cby RNAi almost completely blocks adipogenesis of 3T3-L1 cells. These preliminary data strongly argue that Cby is an essential proadipogenic factor. The long-term goal of this application is to elucidate the role of Cby in adipose tissue development. We propose to analyze adipose tissues in Cby-/- mice, investigate adipogenic potential of Cby-/- mouse embryonic fibroblasts in vitro, and chracterize Cby using preadipocyte and pluripotent mesenchymal stem cells. Our research offers hope that blocking Cby's activity may be an effective therapy for obesity and its associated disorders.