Effects of Wnt/β-catenin signaling on adipocytes

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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.