Tcf21 and visceral adipose tissue development and expansion

Tcf21 和内脏脂肪组织的发育和扩张

• 批准号: 9813320
• 负责人: Xing Fu
• 金额: $ 40.94万
• 依托单位: LOUISIANA STATE UNIV AGRICULTURAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2023-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9813320
• 关键词: Adipocytes; Adipose tissue; Affect; Algorithms; Alleles; Anatomy; BHLH Protein; Binding Sites; Brown Fat; Categories; Cells; Complementary DNA; Development; Epithelial; Exons; Funding; Gene Expression Profiling; Genes; Genetic; Glucose; Goals; Hyperplasia; Insulin Resistance; Internal Ribosome Entry Site; Knock-out; Light; Location; Mediating; Mesenchymal; Mesothelium; Metabolic Diseases; Metabolism; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Nutrient; Organ; Organism; Overnutrition; Pathologic; Plasma; Platelet-Derived Growth Factor alpha Receptor; Process; Promoter Regions; Reagent; Regulation; Reporter; Reporting; Research; Role; Signal Pathway; Site; Stem cells; Tamoxifen; Testing; Therapeutic; Time; Tissue Expansion; Transgenes; Visceral; base; cell fate specification; design; experimental study; gain of function; gene function; in vivo; lipid biosynthesis; loss of function; new therapeutic target; novel; overexpression; promoter; public health relevance; subcutaneous; targeted treatment; tool; transcription factor; transcriptome; uptake

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.

白色脂肪组织分为两类，内脏脂肪组织(VAT)和 皮下脂肪组织(SAT)，基于其解剖位置。一种特定的正相关 已经提出病理性增值税扩张和胰岛素抵抗之间的关系，这使得增值税成为一种 治疗2型糖尿病(T2D)等代谢性疾病的潜在靶点。因为有益于 SAT对新陈代谢的影响，特别是针对增值税特异性调节的研究 需要在不影响SAT的情况下进行脂肪生成，以进一步阐明VAT之间的具体关系 和胰岛素抵抗，并设计适当的增值税靶向治疗策略。TCF21是最近推出的 鉴定了VAT中唯一表达的碱性螺旋-环-螺旋转录因子。其表达方式 在SAT和棕色脂肪组织(BAT)中可以忽略不计。据报道，TCF21对细胞是至关重要的 不同内脏器官中间充质细胞的命运指定和扩增 发展。虽然机制尚不清楚，但建议TCF21促进 上皮-间充质转化(EMT)和祖细胞的增殖，这两个过程也 增值税开发和扩张所需。使用基序发现算法，我们识别了多个 血小板衍生生长因子受体基因启动子中可能的TCF21结合位点 α(PDGFRα)，是一种在祖细胞中广泛表达的基因，可以分化为脂肪细胞。在这 应用、实验研究TCF21在增值税中的功能作用 开发和扩展，并研究TCF21在增值税中的功能作用是否需要PDGFRα。 拟议研究的中心假设是TCF21促进命运规范和 靶向PDGFRα对VAT中造脂祖细胞增殖的影响这样做的目的是 建议阐明TCF21在分子、细胞和细胞中发挥功能的机制 和生物体水平，并探索其治疗潜力。在目标1中，使用TCF21的新型小鼠品系 谱系特异的他莫昔芬诱导的TCF21基因敲除或过表达，以及TCF21谱系追踪将 用来严格审查TCF21在增值税发展和扩大中的职能作用。 通过靶向TCF21治疗代谢紊乱的可行性也将被研究。在AIM #2，PDGFRA-loxP小鼠将与目标1中描述的小鼠品系杂交，以研究 PDGFRα在TCF21中规定增值税的发展和扩大。