Tcf21 and visceral adipose tissue development and expansion

白色脂肪组织（WAT）分为两类，内脏脂肪组织（VAT）和 皮下脂肪组织（SAT），基于其解剖位置。特定的正相关 在病理性增值税扩张和胰岛素抵抗之间存在联系，这使得增值税成为 作为治疗代谢性疾病如2型糖尿病（T2 D）的潜在靶点。由于有益的 SAT对代谢的影响，研究特别侧重于VAT特异性调节， 脂肪形成而不影响SAT需要进一步阐明增值税之间的具体关系， 和胰岛素抵抗，并设计适当的VAT靶向治疗策略。TCF 21是一个最近 鉴定了只在VAT中表达的碱性螺旋-环-螺旋转录因子。其表达 在SAT和棕色脂肪组织（BAT）中可以忽略。据报道，Tcf 21对细胞的生长至关重要， 期间存在于几个内脏器官中的间充质细胞的命运特化和扩增 发展虽然其机制尚不清楚，但Tcf 21可能促进了细胞凋亡。 上皮-间充质转化（EMT）和祖细胞增殖，这两个过程还 增值税的发展和扩大所需的。使用基序发现算法，我们确定了多个 编码血小板衍生生长因子受体的基因启动子中推定的Tcf 21结合位点 α（PDGFRα），一种在祖细胞中广泛表达的基因，可产生脂肪细胞。在这 应用，实验提出了研究Tcf 21在VAT中的功能作用 开发和扩展，并研究Tcf 21在VAT中的功能作用是否需要PDGFRα。 所提出的研究的中心假设是Tcf 21促进命运特化， 通过靶向PDGFRα抑制VAT中成脂祖细胞的增殖。的目的 我们的建议是阐明Tcf 21在分子、细胞和免疫系统中发挥其功能的机制。 和器官水平，并探讨其治疗潜力。在目标#1中，具有Tcf 21的新型小鼠系 谱系特异性他莫昔芬诱导的Tcf 21敲除或过表达，Tcf 21谱系追踪将 用于严格审查Tcf 21在增值税发展和扩展中的功能作用。 还将研究通过靶向Tcf 21治疗代谢紊乱的可行性。在Aim中 #2，将Pdgfra-LoxP小鼠与目标#1中描述的小鼠系杂交，以研究以下的必要性： PDGFRα在Tcf 21调节VAT中的发展和扩展。

White adipose tissue (WAT) is divided into two categories, visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), based on their anatomical locations. A specific positive correlation has been suggested between pathologic VAT expansion and insulin resistance, which makes VAT a potential target for treating metabolic diseases such as type 2 diabetes (T2D). Because of the beneficial effect of SAT on metabolism, research specifically focusing on the VAT-specific regulation of adipogenesis without affecting SAT is needed to further elucidate the specific relationship between VAT and insulin resistance and design appropriate VAT-targeted therapeutic strategies. Tcf21 is a recently identified basic helix-loop-helix transcription factor exclusively expressed in VAT. Its expression in SAT and brown adipose tissue (BAT) is negligible. It was reported that Tcf21 is critical for the cell fate specification and expansion of mesenchymal cells residing in several visceral organs during development. Although the mechanism is still not clear, it is suggested that Tcf21 promotes the epithelial-mesenchymal transition (EMT) and proliferation of progenitor cells, the two processes also required for VAT development and expansion. Using motif-finding algorithms, we identified multiple putative Tcf21 binding sites in the promoter of the gene encoding platelet-derived growth factor receptor α (PDGFRα), a gene widely expressed in progenitor cells that can give rise to adipocytes. In this application, experiments are proposed to investigate the functional role of Tcf21 in VAT development and expansion, and study if the functional role of Tcf21 in VAT requires PDGFRα. The central hypothesis of the proposed studies is that Tcf21 promotes the fate specification and hyperplasia of adipogenic progenitor cells in VAT through targeting PDGFRα. The objective of this proposal is to elucidate the mechanisms by which Tcf21 fulfills its functions at the molecular, cellular and organismic levels, and to explore its therapeutic potential. In Aim #1, novel mouse lines with Tcf21 lineage-specific tamoxifen-inducible Tcf21 knockout or overexpression, and Tcf21 lineage tracing will be used to rigorously examine the functional role of Tcf21 in the development and expansion of VAT. The feasibility of treating metabolic disorder through targeting Tcf21 will also be investigated. In Aim #2, Pdgfra-LoxP mice will be crossed with mouse lines described in Aim #1 to study the necessity of PDGFRα in the Tcf21 regulation of VAT development and expansion.