Role of Beta-Catenin Antagonist Chibby in Adipogenesis

β-连环蛋白拮抗剂 Chibby 在脂肪生成中的作用

• 批准号: 7288066
• 负责人: KEN-ICHI TAKEMARU
• 金额: $ 2.62万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7288066
• 关键词: 3T3 cells; Wnt gene /protein; adipocytes; adipose tissue; athymic mouse; brown fat; cadherins; cell differentiation; developmental genetics; fibroblasts; genetic transcription; histogenesis; laboratory mouse; stem cells; tissue /cell culture

DESCRIPTION (provided by applicant): 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/¿-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 ¿-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 ¿-catenin and represses ¿-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 characterize 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.

描述（由申请人提供）：肥胖是美国和其他西方国家的一个主要健康问题，会增加患糖尿病、心血管疾病和多种癌症的风险，相反，脂肪萎缩（脂肪组织缺乏）也与之相关。因此，了解调节脂肪细胞分化的细胞和分子基础对于制定预防和治疗这些疾病的综合治疗策略是必要的。通过过度表达研究，β-连环蛋白途径已被证明可以抑制脂肪生成，同时维持分裂前脂肪细胞状态，但其生理重要性仍有待阐明。 -连环蛋白相关拮抗剂，称为 Chibby (Cby) 是一种在整个进化过程中保守的核蛋白。 -连环蛋白并抑制 ¿ -catenin 通过与 Lef-1 竞争介导的转录激活，我们进一步证明 Cby 功能的丧失会导致果蝇中该通路的过度激活。出乎意料的是，使用培养的 3T3-L1 前脂肪细胞，我们发现 Cby 蛋白水平增加。此外，Cby 的异位表达会引起自发分化，相反，Cby RNAi 几乎完全阻断 3T3-L1 细胞的脂肪形成。这些初步数据有力地表明，Cby 是一种重要的促脂肪形成因子。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-/- 小鼠胚胎的脂肪形成潜力。我们的研究为阻断 Cby 的活性可能成为治疗肥胖及其相关疾病的有效疗法带来了希望。