Deletion of angiotensin II type 2 receptor accelerates adipogenesis in murine mesenchymal stem cells via Wnt10b/beta-catenin signaling

  • Lab Invest. 2016 Aug;96(8):909-17. doi: 10.1038/labinvest.2016.66.
Kenichi Matsushita  1  2 ,  Yaojiong Wu  1 ,  Richard E Pratt  1 ,  Victor J Dzau  1  3
Affiliations
  • 1. Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
  • 2. Division of Cardiology, Second Department of Internal Medicine, Kyorin University School of Medicine, Tokyo, Japan.
  • 3. National Academy of Medicine, Washington, DC, USA.
PMID: 27295344 DOI: 10.1038/labinvest.2016.66
Abstract

Recent evidence suggests that the renin-angiotensin system (Ras) has 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 (AT2R) promotes adipogenesis in human MSCs. However, the definitive roles of AT2R and how AT2R functions in adipogenesis remains unknown. To this end, we employed AT2R-null murine MSCs to characterize how AT2R affects the differentiation of MSCs into adipocytes. Murine MSCs were isolated from AT2R-null mice and wild-type littermates, grown to confluency, and then differentiated into adipocytes. Adipogenesis was quantitated by assessing the lipid droplet accumulation. Using the lipophilic Fluorescent Dye, the AT2R-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 AT2R-null cells (202.7±14.1% vs littermate). We also examined the expression of adipogenic marker genes by quantitative RT-PCR. The AT2R-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 has an important inhibitory role in adipogenesis. The AT2R-null group exhibited significantly decreased Wnt10b expression accompanied by decreased beta-catenin (vs littermate). Our results thus revealed that the AT2R 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.