117-OR: Inhibition of Endothelial ROCK2 Induces Fat Browning and Improves Metabolic Dysfunction
Authors: TAKEDA YUSUKE , MATOBA KEIICHIRO , NAGAI YOSUKE , UKICHI RIKAKO , SEKIGUCHI KENSUKE , AKAMINE TOMOYO , KANAZAWA YASUSHI , UTSUNOMIYA KAZUNORI , NISHIMURA RIMEI 
Published: June 2021

Intraperitoneal fat is regarded as an important risk factor for dyslipidemia, impaired glucose tolerance, and coronary heart diseases. However, the detailed molecular mechanisms in obesity remain to be understood. The small GTPase Rho and its downstream effector, Rho-kinase (ROCK), regulate various cellular functions, including expression of genes, cell adhesion, and organization of the actin cytoskeleton. Recent studies have shown that Rho/ROCK signaling is firmly associated with diabetic vascular complications. There are two isoforms of ROCK, ROCK1 and ROCK2. Systemic gene deletion studies in mice show that each isoform have a unique role in modulating cellular function. In this study, we examined specific roles of endothelial ROCK2 in the formation of obesity. We generated endothelium-specific ROCK2 knockout mice (ER2KO) by breeding ROCK2 floxed mice with mice expressing VE-cadherin-Cre recombinase. ER2KO are resistant to weight gain and glucose intolerance induced by high-fat diet. White adipose tissue (WAT) weight was lower in ER2KO 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. Intriguingly, we observed an increase of mRNA expression of browning markers (e.g., CIDEA, UCP1) and M2 macrophage-restricted transcripts in WAT of ER2KO regardless of whether they had been fed a normal chow or high-fat diet. We next investigated metabolic rate of mice. ER2KO showed increased body temperature and gained less weight after overnight fasting.
In summary, 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.

Disclosure
Y. Takeda: None. K. Matoba: Research Support; Self; Eli Lilly Japan K. K. Y. Nagai: None. R. Ukichi: None. K. Sekiguchi: None. T. Akamine: None. Y. Kanazawa: None. K. Utsunomiya: None. R. Nishimura: Speaker’s Bureau; Self; Abbott Japan Co., Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly Japan K. K., Kissei Pharmaceutical Co., Ltd., Medtronic, MSD Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited.

Funding
Japan Society for the Promotion of Science (to K.M., R.N.); MSD Life Science Foundation (to K.M.); Takeda Science Foundation (to K.M.); Suzuken Memorial Foundation (to K.M.); Sanofi KK (to K.M.); Mitsubishi Tanabe Pharma Corporation (to K.M.); Takeda Pharmaceutical Company (to K.M.); Terumo Medical Corporation (to K.U.); Novo Nordisk Pharma, Inc. (to K.U.); Taisho Pharmaceutical (to K.U.); Boehringer Ingelheim (to K.U.); Hakko Kirin (to K.U.); Sumitomo Dainippon Pharma (to K.U.); Ono Pharmaceutical A/S (to K.U.); Astellas Pharma (to R.N.); Nippon Boehringer Ingelheim (to R.N.); Eli Lilly Japan KK (to R.N.); Kissei Pharmaceuticals (to R.N.); Medtronic Japan (to R.N.); MSD (to R.N.); Novartis Pharma KK (to R.N.); Novo Nordisk Pharma (to R.N.)