Roles for Wnt signaling in adipose tissue

描述(申请人提供)：我们研究项目的目标是确定细胞外信号调节脂肪细胞分化和代谢的分子机制。在过去的资助期间，我们进行了新的研究，证明Wnt10b信号作为脂肪形成的抑制因子在培养的前脂肪细胞和转基因小鼠中具有重要作用。我们的研究表明，WNT10b在前脂肪细胞和间质血管细胞中都有表达，并且WNT10b在诱导成脂后迅速减少。WNT10b通过抑制C/EBPA和PPARβ的表达来抑制脂肪的生成，内源性WNT10b与抗血清中和刺激前脂肪细胞的成脂。在脂肪组织中表达WNT10b的转基因小鼠(FABP4-WNT10b)体内总脂肪减少约50%，内脏脂肪减少约60%。FABP4-WNT10b小鼠对饮食诱导的肥胖和遗传性肥胖具有抵抗力，这些小鼠比对照组更耐葡萄糖和胰岛素敏感。我们的研究已经将WNT10b的作用从简单的抑制前脂肪细胞分化扩展到调节多潜能干细胞的命运。因此，FABP4-WNT10b小鼠不仅脂肪组织减少，而且骨小梁增加了四倍。除了WNT10b直接刺激成骨细胞的生成和减少骨髓中的间充质祖细胞的脂肪生成外，成骨细胞活性的增加似乎也是通过一种新的机制来介导的，即通过哺乳动物靶点雷帕霉素和蛋白质翻译。进一步支持Wnt10b在控制间充质前体命运中的关键作用来自我们的观察，Wnt10b-/-小鼠的骨小梁减少了约30%，血清成骨细胞标志物也相应减少。虽然到目前为止，我们的重点是Wnt/？-catenin如何影响发育过程，但我们的研究表明，Wnt信号在成熟脂肪细胞的功能中具有额外的作用。这些研究使我们假设Wnts信号在脂肪细胞中通过WnT受体卷曲4来调节脂肪细胞和全身新陈代谢。本申请中提出的实验将系统地建立在我们过去的研究基础上，以更详细地了解Wnt信号在脂肪细胞和脂肪组织中的分子、细胞和整个动物生物学。公共卫生相关性：肥胖和体重增加与糖尿病和许多其他医疗问题有关，包括心血管疾病和某些癌症。肥胖的特征是由于现有脂肪细胞的大小增加而导致脂肪组织的增加，以及新的祖细胞的招募。WNT信号参与了这两个过程；然而，其机制还不是很清楚。因此，这项拟议的研究将为脂肪细胞和全身新陈代谢提供重要的见解，并可能为肥胖和II型糖尿病的医学问题提供见解，这两个问题是美国的两大健康风险。

DESCRIPTION (provided by applicant): The goal of our research program is to determine molecular mechanisms whereby extracellular signals regulate adipocyte differentiation and metabolism. In the past funding period, we have performed novel studies demonstrating an important role for Wnt10b 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 that Wnt10b decreases rapidly upon induction of adipogenesis. Wnt10b blocks adipogenesis by inhibiting expression of C/EBPa and PPAR?, and neutralization of endogenous Wnt10b with antisera stimulates adipogenesis of preadipocytes. Transgenic mice expressing Wnt10b in adipose tissue (FABP4-Wnt10b) have ~50% less total body fat and a ~60% reduction in visceral fat depots. FABP4-Wnt10b mice are resistant to diet-induced and genetic-obesity, and these mice are more glucose-tolerant and insulin-sensitive than controls. Our studies have expanded the role for Wnt10b from simple inhibition of preadipocyte differentiation to modulating fate of multipotent stem cells. Thus, FABP4-Wnt10b mice not only have less adipose tissue, but they have a four-fold increase in trabecular bone. In addition to a direct effect of Wnt10b to stimulate osteoblastogenesis and decrease adipogenesis of resident mesenchymal progenitor cells in marrow, increased osteoblast activity also appears to be mediated by a novel mechanism through mammalian target of rapamycin and protein translation. Further support for a critical role for Wnt10b in governing fate of mesenchymal precursors comes from our observations that Wnt10b -/- mice have ~30% less trabecular bone and a corresponding decrease in serum osteoblast markers. While our focus to date has been on how Wnt/¿-catenin influences developmental processes, our studies suggest that Wnt signaling has additional roles in functions of the mature adipocyte. These studies have led us to hypothesize that Wnts signal in adipocyte through the Wnt receptor frizzled 4 to regulate adipocyte and whole body metabolism. The experiments proposed in this application will systematically build on our past studies to understand in greater detail the molecular, cellular and whole animal biology of Wnt signaling in adipocytes and adipose tissue. PUBLIC HEALTH RELEVANCE: Obesity and weight gain are associated with diabetes and many other medical problems including cardiovascular disease and certain cancers. Obesity is characterized by an increase in adipose tissue due to increase in size of existing fat cells, and recruitment of new progenitors. Wnt signaling is involved in both of these processes; however, the mechanisms are not well understood. Thus, the proposed research will provide important insights into adipocyte and whole body metabolism, and potentially provide insight into the medical problems of obesity and type II diabetes, two major health risks in the United States.