Deletion of Angiotensin II Type 2 Receptor Accelerates Adipogenesis in Murine Mesenchymal Stem Cells via Wnt10b/beta-catenin Signaling

Recent evidence suggests that the renin-angiotensin system (RAS) plays a vital role in adipocyte biology and the pathophysiology of metabolic syndrome. Obesity is the main culprit of metabolic syndrome and mesenchymal stem cells (MSCs) have been forwarded as a major source of adipocyte generation. Previously we reported that MSCs have a local RAS and that pharmacological blockade of angiotensin II type 2 receptor (AT(2)R) promotes adipogenesis in human MSCs. However, the definitive roles of AT(2)R and how AT(2)R functions in adipogenesis remains unknown. To this end, we employed AT(2)R-null murine MSCs to characterize how AT(2)R affects the differentiation of MSCs to adipocytes. Murine MSCs were isolated from AT(2)R-null mice and wild-type littermates, grown to confluency, and then differentiated into adipocytes. Adipogenesis was quantitated by assessing lipid droplet accumulation. Using the lipophilic fluorescent dye, the AT(2)R-null cells showed significantly increased total fluorescence (261.6 ± 49.6 % vs. littermate) on day 7. Oil red O staining followed by extraction of the absorbed dye and measurement of the absorbance on day 14 also exhibited significantly increased lipid droplet accumulation in the AT(2)R-null cells (202.7 ± 14.1 % vs. littermate). We also examined the expression of adipogenic marker genes by quantitative RT-PCR. The AT(2)R-null group exhibited significantly increased expression of PPAR-gamma, fatty acid synthase, and adiponectin (vs. littermate). We further examined the role of Wnt10b/beta-catenin signaling, which reportedly plays an important inhibitory role in adipogenesis. The AT(2)R-null group exhibited significantly decreased Wnt10b expression accompanied by decreased beta-catenin (vs. littermate). Our results thus revealed that the AT(2)R inhibits adipogenic differentiation in murine MSCs. Moreover, this inhibitory effect is associated with Wnt10b/beta-catenin signaling. These results provide important insights into the pathophysiology of obesity and obesity-related consequences such as metabolic syndrome, hinting at possible future therapies.