Wnt/beta-catenin signaling in adipogenesis and metabolism

Abstract

Adipocyte differentiation consists of a complex series of events in which scores of cellular and extracellular factors interact to transform a fibroblast-like preadipocyte into a mature, lipid-filled adipocyte. Many of the pathways influencing this process have been identified using well-characterized preadipocyte culture systems and have subsequently been confirmed in animal models. Research conducted over the past decade has established the Wnt/beta-catenin signaling pathway as an important regulator of adipocyte differentiation. While initial reports implicated activators of Wnt/beta-catenin signaling as potent inhibitors of adipogenesis, recent investigations of mesenchymal cell fate, obesity, and type 2 diabetes highlight significant additional roles for Wnt signaling in metabolism and adipocyte biology.

Figure 1. Wnt/β-catenin signaling is a central pathway regulating adipogenesis

Wnt/β-catenin signaling in preadipocytes is initiated by expression of Wnt10b, Wnt10a, and Wnt6. Binding of these Wnts to transmembrane frizzled receptors and LRP coreceptors inhibits GSK3β leading to hypophosphorylation and stabilization of β-catenin in the cytoplasm. β-catenin is then translocated to the nucleus where it binds TCF/LEF transcription factors and activates downstream targets to inhibit preadipocyte differentiation. Factors from other inhibitory pathways converge on the Wnt/β-catenin pathway to block adipocyte conversion. TNFα signals through its receptor, TNFα receptor-1, to stabilize β-catenin and activate downstream pathways. Testosterone inhibits adipogenesis in part by stimulating interactions between androgen receptor and β-catenin. This complex travels to the nucleus to promote β-catenin-mediated gene transcription. DKK1 and Wnt5b are transiently induced during adipogenesis and stimulate preadipocyte differentiation. DKK1 prevents Wnt signaling by inhibiting LRP coreceptors, while Wnt5b promotes differentiation through an unknown mechanism. As adipogenesis proceeds, the expression of another Wnt inhibitor, Cby, is induced. Cby binds β-catenin in the nucleus and prevents coactivation of TCF/LEF transcription factors. Finally, binding of β-catenin to PPARγ leads to rapid degradation of β-catenin through a mechanism that involves the proteosome. (−) indicates factors that inhibit preadipocyte differentiation and (+) denotes factors that stimulate the process.