Intraperitoneal fat is considered a particularly important risk factor for impaired glucose tolerance, dyslipidemia, and coronary heart diseases. However, the underlying mechanisms in obesity are not fully understood. The small GTPase Rho and its downstream effector, Rho-kinase (ROCK), regulate various cellular functions, including organization of the actin cytoskeleton, cell adhesion and expression of genes. Recent studies have shown that Rho/ROCK signaling is strongly related to diabetic vascular complications. ROCK has two isoforms, ROCK1 and ROCK2. Systemic gene deletion studies in mice suggest that these isoforms have distinctive roles in regulating cellular function. In this study, we investigated specific roles of endothelial ROCK2 in the progression of obesity. We mated ROCK2 floxed mice with VE-cadherin-cre mice to generate endothelial-ROCK2 knockout mice (ER2KO). ER2KO mice are resistant to weight gain and glucose intolerance induced by high fat diet. White adipose tissue (WAT) weight was lower in ER2KO mice compared with wild type mice. Histological analysis revealed that adipose droplets were smaller in ER2KO than wild type mice. Browning, the conversion of WAT to a beige phenotype, activates thermogenic function, suppresses obesity and improves glucose and lipid metabolism. Interestingly, we observed an increase of mRNA expression of browning marker including PPARα, CIDEA, PRDM16, UCP1, and specific markers of M2 macrophages in WAT of ER2KO mice regardless of whether they had been fed a normal chow or high fat diet. Collectively, the present study suggests that endothelial ROCK2 regulates glucose and lipid metabolism by suppressing browning of WAT. ROCK2 could be an important therapeutic target against obesity.
Y. Takeda: None. K. Matoba: Research Support; Self; Sanofi K.K., Takeda Pharmaceutical Company Limited. D. Kawanami: None. Y. Nagai: None. Y. Kanazawa: None. R. Nishimura: Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc. Speaker’s Bureau; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly Japan K.K., Medtronic, Merck & Co., Inc., Novo Nordisk Inc., Sanofi K.K., Takeda Pharmaceutical Company Limited.