Novel transcription factor for UCP-1 expression in brown fat

描述（由申请人提供）：肥胖是一种全球性的健康流行病，与寿命缩短和2型糖尿病和心脏病等代谢性疾病的发病率增加有关。脂肪有两种。白色脂肪以脂肪酸的形式储存能量，棕色脂肪是哺乳动物的产热器官。棕色脂肪最近被证明存在于成年人中——这一发现引起了相当大的兴趣，因为棕色脂肪特异性基因表达的增加似乎再次保护了肥胖和代谢综合征。虽然已知棕色脂肪的生热作用可以使能量平衡倾向于使用而不是储存，但在分子水平上如何以及为什么发生这种情况尚不清楚。此外，抗肥胖策略可能包括增加棕色脂肪特异性产热基因的表达，包括解偶联蛋白-1 （UCP1）以及棕色脂肪的形成。由于对棕色脂肪转录网络知之甚少，因此更好地了解这个网络是该研究项目的直接目标。我们的实验室发现了一种新的锌指转录因子，该转录因子优先在棕色脂肪中高水平表达，我们的初步数据表明，该转录因子的一个靶点（指定为B2）是UCP1，这是已知最重要的产热基因，仅存在于棕色脂肪中，对棕色脂肪产热至关重要。这项NRSA奖学金的目标是了解B2的生物学及其在棕色脂肪中的作用。目的1试图利用生化和分子方法确定UCP1启动子中B2的DNA结合位点。目的2通过串联亲和纯化和质谱技术鉴定B2蛋白的相互作用伙伴。最后，目的3是通过培养和分析B2敲除小鼠来评估B2在体内的作用。这些研究将为新近复苏的棕色脂肪生物学领域做出重要贡献，并可能为棕色脂肪在肥胖中的研究提供新的方向。

DESCRIPTION (provided by applicant): Obesity is a global health epidemic that is associated with decreased life span and increased incidence of metabolic diseases like type 2 diabetes and heart disease. Two types of fat exist. White fat stores energy in the form of fatty acids, and brown fat is the mammalian thermogenic organ. Brown fat has recently proven to be present in adult humans-a finding which has drawn considerable interest because increases in brown fat- specific gene expression appear to protect again obesity and metabolic syndrome. While it is known that brown fat thermogenesis can tip the energy balance in favor of use rather than storage, how and why this occurs is unclear at the molecular level. Furthermore, anti-obesity strategies could include increasing expression of brown-fat specific thermogenic genes including uncoupling protein-1 (UCP1) as well as brown fat formation. Since not much is known about the brown fat transcriptional network, a better understanding of this fnetwork is the immediate goal for the research project. Our lab has identified a novel zinc finger transcription factor that is preferentially expressed in brown fat at a high level, and our preliminary data indicate one target of this transcription factor (designated as B2) is UCP1, the most important known thermogenic gene, which is found exclusively in brown fat and critical for brown fat thermogenesis. The goal of the work to be undertaken in this NRSA fellowship is to understand the biology of B2 and its role in brown fat. Aim 1 seeks to define the DNA binding site for B2 in the UCP1 promoter using biochemical and molecular approaches. Aim 2 is to identify the protein interaction partners of B2 by tandem affinity purification and mass spectrometry. Finally, Aim 3 is to assess the role of B2 in vivo by developing and analyzing B2 knockout mice. These studies will make an important contribution to the newly resurgent field of brown fat biology by characterizing the novel transcription factor B2 and may provide new directions for the study of brown fat in obesity. PUBLIC HEALTH RELEVANCE: The prevalence of obesity in our society is unmistakable, and people with the disease have a shorter lifespan and an increased chance of diabetes and heart disease. This study seeks to understand the genetic regulation of brown fat, which burns fat as heat. By understanding more about brown fat, we may find new treatment targets that would activate this type of fat, burn more fat, and therefore reduce obesity.