Role of B2 in Brown Fat Transcription and Development

描述（由申请人提供）：肥胖症是一种与多种代谢疾病（如2型糖尿病）相关的全球健康流行病。虽然白色脂肪组织（WAT）积累脂肪作为能量储存，过量导致肥胖，但棕色脂肪组织（BAT）通过非颤抖产热将能量耗散为热量。最近，已经证明即使在成年人中也存在大量功能性BAT-这一发现引起了相当大的兴趣，因为BAT活性的增加可能对肥胖有保护作用。诱导产热基因如解偶联蛋白-1（UCP 1）和促进BAT发育可能是肥胖的治疗策略。因此，阐明BAT转录网络至关重要。我们已经确定了一种新的锌指转录因子，B2，这是优先在BAT中表达相比，WAT和其他组织，并诱导显着冷暴露。我们发现B2直接结合并强烈激活UCP 1启动子。推测的B2结合元件被发现在其他BAT富集基因的启动子区域中，并且我们检测到B2对PGC 1 β启动子的结合和激活。在棕色脂肪细胞分化过程中B2表达增加。我们发现B2的组成型表达增强了棕色脂肪细胞的分化，而shRNA敲低抑制了分化。我们产生的B2基因敲除小鼠显示BAT质量急剧下降，棕色脂肪细胞形态异常，UCP 1和其他富含BAT的基因表达降低。本研究的目的是了解B2如何激活UCP 1和其他BAT基因，以及B2在BAT发育和功能中的作用。目的1是研究B2激活UCP 1和其他BAT富集基因的分子机制，以及B2在冷暴露后是如何被诱导的。目的2：探讨B2在体外棕色脂肪细胞分化中的作用。目的3是在小鼠中采用功能获得和功能丧失的方法来检查B2在体内的功能。这项研究将有助于BAT生物学的新兴领域，并可能为肥胖治疗提供新的靶点。

DESCRIPTION (provided by applicant): Obesity is a global health epidemic associated with several metabolic diseases, such as type 2 diabetes. While white adipose tissue (WAT) accumulates fat as energy storage that in excess results in obesity, brown adipose tissue (BAT) dissipates energy as heat via non-shivering thermogenesis. Recently, substantial functional BAT has been proven to be present even in adult humans-a finding which has generated considerable interest, since an increase in BAT activity may be protective against obesity. Inducing thermogenic genes such as uncoupling protein-1 (UCP1) and promoting BAT development could be therapeutic strategies for obesity. Thus, it is critical to elucidate the BAT transcriptional network. We have identified a novel zinc finger transcription factor, B2, which is preferentially expressed in BAT compared to WAT and other tissues and is induced drastically upon cold exposure. We found that B2 directly binds to and robustly activates the UCP1 promoter. The putative B2 binding element is found in the promoter regions of other BAT-enriched genes, and we detected binding and activation of PGC1� promoter by B2. B2 expression is increased during brown adipocyte differentiation. We found that constitutive expression of B2 enhances brown adipocyte differentiation, whereas shRNA knockdown inhibits differentiation. The B2 knockout mice that we have generated show drastically decreased BAT mass with abnormal brown adipocyte morphology and decreased expression of UCP1 and other BAT-enriched genes. The goal of this research is to understand how B2 activates UCP1 and other BAT genes and the role of B2 in the BAT development and function. Aim 1 is to examine the molecular mechanisms underlying B2 activation of UCP1 and other BAT-enriched genes and how B2 is induced upon cold exposure. Aim 2 is to investigate the role of B2 in brown adipocyte differentiation in vitro. Aim 3 is to employ gain- and loss-of function approaches in mice to examine the function of B2 in vivo. This research will contribute to the emerging field of BAT biology and may provide new targets for obesity therapeutics.