Regulation of adipocyte differentiation and metabolism

脂肪细胞分化和代谢的调节

• 批准号: 7883391
• 负责人: Ormond A MacDougald
• 金额: $ 29.31万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-07-25 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7883391
• 关键词: Adipocytes; Adipose tissue; Aging; Applications Grants; Blood Vessels; Body fat; CCAAT-Enhancer-Binding Protein-alpha; Cell Differentiation process; Cells; Cultured Cells; Development; Diet; Fatty acid glycerol esters; Funding; Genetic; Genetic Transcription; Glucose; Goals; Health; Immune Sera; Individual; Insulin; Laboratories; Life; Marrow; Mediating; Medical; Mesenchymal; Mesenchymal Stem Cells; Metabolism; Molecular; Molecular Analysis; Multipotent Stem Cells; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Osteoblasts; PPAR gamma; Paracrine Communication; Physiological; Play; Process; Production; Regulation; Relative (related person); Repression; Research; Resistance; Risk; Role; Serum; Signal Transduction; Signaling Molecule; Testing; Transgenic Mice; United States; Visceral; Work; adipocyte differentiation; autocrine; energy balance; extracellular; farmer; human SFRP4 protein; inhibitor/antagonist; insight; lipid biosynthesis; novel; paracrine; precursor cell; programs; receptor; research study; substantia spongiosa; transcription factor

DESCRIPTION (provided by applicant): In the past funding period, we have performed novel studies demonstrating an important role for Wnt signaling as an inhibitor of adipogenesis in cultured preadipocytes and in transgenic mice. Our studies have demonstrated that Wnt10b is expressed in preadipocytes and stromal vascular cells and decreases rapidly upon induction of adipogenesis. Further, we found that Wnt10b regulates adipogenesis through suppression of C/EBPalpha and PPARgamma and that inhibition of endogenous Wnt10b with neutralizing antisera stimulates adipogenesis of cultured preadipocytes. Transgenic mice expressing Wnt10b in adipose tissue have reduced adipose tissue. FABP4-Wnt10b mice consuming a high fat diet are resistant to diet-induced and genetic-obesity, and these mice are more glucose-tolerant and insulin-sensitive than controls. Our studies have also expanded the role for Wnt10b from simple inhibition of preadipocyte differentiation to modulating fate of multipotent stem cells. Thus, FABP4-Wnt10b mice have a four-fold increase in trabecular bone. This appears to be a direct effect of Wnt10b to stimulate osteoblastogenesis and decrease adipogenesis of resident mesenchymal progenitor cells in marrow. Further support for a critical role for Wnt10b in governing fate of mesenchymal precursors comes from our observations that Wnt10b -/- mice have approximately 30% less trabecular bone and a corresponding decrease in serum osteoblast markers. Although we have made considerable progress in our studies on the effects of Wnt signaling on adipogenesis, how autocrine and paracrine signals in cultured cells and adipose tissue regulate endogenous Wnt signaling remains unknown. In this competitive renewal of DK51563, we propose experiments to test the hypotheses that Wnt activity in precursor cells is comprised of competing contributions from multiple Wnts and secreted frizzled-related proteins (sFRP) in preadipocytes and adipocytes, and that Wnt signaling inhibits adipogenesis by repressing the expression and/or activity of PPARgamma. Thus, the specific aims of this grant application are to: Specific Aim 1: Investigate activity and regulation of Wnt signaling molecules including Wnts, Fzd, and sFRPs. Specific Aim 2: Investigate mechanisms whereby Wnt signaling inhibits expression of PPARgamma. Successful completion of these specific aims will provide important insight into fat cell differentiation and metabolism, and provide insight into the medical problems of obesity and type II diabetes, two major health risks in the United States.

描述（由申请人提供）：在过去的资金期间，我们进行了新的研究，证明了Wnt信号作为作为培养的前脂肪细胞和转基因小鼠的脂肪生成抑制剂的重要作用。我们的研究表明，Wnt10b在脂肪细胞和基质血管细胞中表达，并在脂肪生成诱导后迅速降低。此外，我们发现WNT10B通过抑制C/eBpalpha和ppargamma来调节脂肪形成，并且用中和抗血清抑制内源性Wnt10b的抑制会刺激培养的前膜细胞的脂肪形成。在脂肪组织中表达WNT10B的转基因小鼠的脂肪组织减少。消耗高脂饮食的Fabp4-Wnt10b小鼠对饮食诱导的和遗传肥胖具有抗性，这些小鼠比对照组更耐葡萄糖和胰岛素敏感。我们的研究还扩大了WNT10B的作用，从对前脂肪细胞分化的简单抑制作用到调节多能干细胞的命运。因此，FABP4-WNT10B小鼠的小梁骨增加了四倍。这似乎是Wnt10b刺激成骨细胞生成并减少骨髓中间充质祖细胞的脂肪形成的直接效应。 WNT10B在间质前体的命运中的关键作用的进一步支持来自我们的观察结果，即Wnt10b - / - 小鼠的小梁骨少约30％，血清成骨细胞标记的相应减少。尽管我们在研究Wnt信号对脂肪生成的影响方面取得了长足的进步，但培养细胞中的自分泌和旁分泌信号如何调节内源性Wnt信号传导仍未知。在DK51563的这种竞争更新中，我们提出了实验，以测试前体细胞中的Wnt活性由多个WNT和分泌的毛线相关蛋白（SFRP）的竞争性贡献组成，并在Preadipocytes和dipocipytes中和脂肪细胞中的作用和脂肪症的表达方式和/或通过dipsips scripress和/scrips/dipa syperage sypares和/scrips/diss/scress/scress/scress/scress/n.因此，本赠款应用的具体目的是：具体目标1：研究Wnt信号分子在内的活动和调节，包括Wnts，FZD和SFRP。特定目标2：研究WNT信号抑制ppargamma表达的机制。这些特定目标的成功完成将为脂肪细胞分化和代谢提供重要的见解，并提供对肥胖和II型糖尿病的医学问题的见解，这是美国两种主要的健康风险。