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（WAT）分为两类，内脏脂肪组织（VAT）和