Effects of Wnt/β-catenin signaling on adipocytes

摘要 肥胖是许多继发性慢性疾病的关键风险因素，包括2型糖尿病和心血管疾病。 疾病。经典的Wnt/β-catenin信号转导通路是间充质细胞的重要调节因子 命运决定和分化，抑制脂肪生成，促进成骨细胞生成。新兴 人类的遗传证据已将各种Wnt通路成员与身体脂肪分布、肥胖和 代谢功能障碍，表明这一途径在终末分化的脂肪细胞中是可行的。的确， 最近在小鼠身上进行的研究发现了令人信服的证据，表明Wnt途径发挥着重要作用 在脂肪细胞代谢中的作用，特别是在肥胖条件下。然而，其确切的功能角色 在这种情况下，Wnt途径及其潜在的分子机制仍不清楚。在我们的初始阶段 我们删除了在终末分化的脂肪细胞中表征这一途径重要性的实验 Wnless，Wnt蛋白分泌的专用细胞内伴侣，或β-连环蛋白，中枢信号转导 培养的脂肪细胞和脂肪组织中的分子经典Wnt途径。这两种方法都揭示了 脂肪细胞来源的Wnts或典型的Wnt/β-catenin信号的丢失协调下调- 调节生脂基因表达，导致新生脂肪生成和脂肪酸受损 单不饱和度。此外，这些对脂代谢的影响是通过抑制Srebf1和MLXIPL介导的， 已知的脂肪生成酶表达的主要转录调节因子。体内缺失Wnless或β- 连环蛋白不影响饮食维持的小鼠的整体新陈代谢。然而，我们的研究揭示了 一种显著的现象，即脂肪组织能够防御脂肪细胞特异性丢失Wnless或β- 通过代偿上调周围基质-血管细胞中的Wnt信号来实现连环蛋白。最后，Long- 长期营养过剩覆盖了这种补偿机制，因此wls-/-和β-cat-/-小鼠都具有抵抗力 减少饮食引起的肥胖，并防止代谢功能障碍。在此，我们建议进行实验，以 进一步研究Wnt信号在脂肪组织中的作用。具体地说，我们将调查这些机制 Wnt/β-catenin通过什么调控脂肪细胞基因表达和细胞功能，以及细胞间Wnt是如何 信号监测和补偿脂肪细胞中Wnt信号的丢失。成功完成 这些目标将提高我们对这个古老的信号通路如何对生理学至关重要的理解 和脂肪组织的病理生理学。

Abstract Obesity is a key risk factor for many secondary chronic illnesses, including type 2 diabetes and cardiovascular disease. Canonical Wnt/β-catenin signaling is well-established as an important regulator of mesenchymal cell fate determination and differentiation, inhibiting adipogenesis and promoting osteoblastogenesis. Emerging genetic evidence in humans has linked various Wnt pathway members to body fat distribution, obesity, and metabolic dysfunction, suggesting that this pathway is operative in terminally-differentiated adipocytes. Indeed, recent studies in mice have uncovered compelling evidence suggesting that the Wnt pathway plays important roles in adipocyte metabolism, particularly under obesogenic conditions. However, the exact functional roles of the Wnt pathway and its underlying molecular mechanisms in this context remain unclear. In our initial experiments to characterize the importance of this pathway in terminally-differentiated adipocytes, we deleted Wntless, a dedicated intracellular chaperone for Wnt protein secretion, or β-catenin, the central signaling molecule canonical Wnt pathway from cultured adipocytes and in adipose tissue. Both approaches revealed that loss of adipocyte-derived Wnts or canonical Wnt/β-catenin signaling in adipocytes coordinately down- regulates lipogenic gene expression, resulting in impaired de novo lipogenesis and fatty acid monounsaturation. Further, these effects on lipid metabolism are mediated by repression of Srebf1 and Mlxipl, known master transcriptional regulators of lipogenic enzyme expression. In vivo, deletion of Wntless or β- catenin does not influence global metabolism in mice maintained on chow diet. However, our studies revealed a striking phenomenon by which adipose tissues are able to defend adipocyte-specific loss of Wntless or β- catenin by compensatory up-regulation of Wnt signaling in surrounding stromal-vascular cells. Finally, long- term overnutrition overrides this compensatory mechanism, such that both Wls-/- and β-cat-/- mice are resistant to diet-induced obesity and protected from metabolic dysfunction. Herein we propose experiments to investigate further the roles of Wnt signaling in adipose tissue. Specifically, we will investigate the mechanisms by which Wnt/β-catenin regulates adipocyte gene expression and cell functions, and how intercellular Wnt signaling monitors and compensates for the loss of Wnt signaling in adipocytes. Successful completion of these aims will improve our understanding of how this ancient signaling pathway is critical for the physiology and pathophysiology of adipose tissues.