Investigating the Roles of Wnt Signaling in Mature Adipocyte Function

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 also 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 due to complexities of Wnt signaling and differences in experimental models, approaches, and results.

My dissertation work endeavored to unravel the unique contributions of Wnt pathway members to adipocyte metabolism. To this end, I generated novel cultured cell and mouse models to functionally characterize the differential roles of two key pathway members, Wntless and β-catenin, in terminally-differentiated adipocytes. Deletion of Wntless, a dedicated intracellular chaperone for Wnt proteins, allowed me to investigate the functional roles of both canonical and non-canonical Wnts secreted from adipocytes, whereas loss of β-catenin allowed me to specifically interrogate the contribution of canonical Wnt signaling to adipocyte function.

These studies revealed for the first time that loss of adipocyte-derived Wnts or canonical Wnt/β-catenin signaling in adipocytes coordinately down-regulates a wide network of lipogenic genes, resulting in impaired de novo lipogenesis and fatty acid desaturation. Further, these effects on lipid metabolism are mediated by repression of Srebf1 and Mlxipl, known master transcriptional regulators of lipogenic enzyme expression. At first glance, Wntless and β-catenin do not appear to influence global metabolism in mice maintained on chow diet. However, my studies revealed a striking phenomenon by which adipose tissues defend adipocyte-specific loss of Wntless or β-catenin through compensatory up-regulation of Wnt signaling in neighboring stromal-vascular cells. Finally, long-term overnutrition overrides this compensatory mechanism, revealing that both adipocyte-specific Wntless and β-catenin knockout mice are resistant to diet-induced obesity, adipocyte hypertrophy, and metabolic dysfunction.

Taken together, my doctoral findings demonstrate that Wnt signaling in adipocytes is required for fatty acid and glucose metabolism. In addition, adipose tissues rigorously defend Wnt signaling homeostasis under standard nutritional conditions, underscoring the critical importance of this pathway in mature adipocyte metabolism and adipose tissue function. Finally, given the evolutionary conservation and ubiquitous nature of this pathway, it is likely that the findings herein, including compelling evidence of Wnt-mediated cross-talk between diverse cell types, will be widely applicable to the biology of other tissues.