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（适用提供）：肥胖是美国和其他西方国家的主要健康问题，增加了患糖尿病，心血管疾病和几种类型的癌症的风险。相比之下，脂肪植物缺乏脂肪组织，也与糖尿病和各种代谢异常有关。这是必须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全面治疗策略是必要的。典型的Wnt/® -Catenin途径已被证明可以抑制脂肪形成，同时通过过表达研究保持了分裂的前卵形前状态。但是，它的身体重要性仍有待阐明。我们报道了一种新颖的�-加丁蛋白相关的拮抗剂，称为Chibby（CBY）。 CBY是一种核蛋白，在整个进化过程中都是保守的。我们表明，CBY与» - 卡宁蛋白的C端激活结构域相互作用，并通过与LEF-1竞争，与抑制作用�-Catenin介导的转录激活相互作用。我们进一步证明，CBY功能的丧失会导致果蝇中的途径过度激活。为了深入了解脊椎动物发育过程中CBY的功能以及人类疾病，我们创建了CBY-NULL（CBY - / - ）小鼠。出乎意料的是，这些小鼠暴露了脂肪的降低。使用培养的3T3-L1前脂肪细胞，我们发现在脂肪生成过程中，CBY蛋白水平升高。此外，CBY的生态表达会引起赞助分化，相反，CBY RNAi几乎完全阻止了3T3-L1细胞的脂肪形成。这些初步数据强烈认为CBY是必不可少的跨次生构成因子。该应用的长期目标是阐明CBY在脂肪组织发育中的作用。我们建议分析CBY - / - 小鼠中的脂肪时序，研究CBY - / - 小鼠胚胎成纤维细胞体外的脂肪形成潜力，并使用前脂肪细胞和多能间质干细胞来表征CBY。我们的研究希望阻止CBY的活动可能是肥胖及其相关疾病的有效疗法。