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Introduction and Objective: The vascular endothelium has evolved anatomical and functional network between adipocytes in adipose tissue, secreting several bioactive substances to orchestrate energy homeostasis. However, when compared with other organs, relatively little is known about the molecular machinery that directly governs the crosstalk system in adipose tissue. Although previous studies have defined Rho-associated, coiled-coil-containing protein kinase 2 (ROCK2) as an inducer of vascular inflammation, a direct role for the endothelium-adipocyte network in physiological and pathophysiological states has not been previously established. Method: To clarify the tissue-specific role of ROCK2, we generated mice lacking vascular endothelial ROCK2. Normal adipocytes were incubated with a conditioned medium obtained from ROCK2-deficient human adipose tissue vascular endothelial cells. Result: We show in normal adipose tissue samples that ROCK2 is expressed in vascular endothelial cells. Mice lacking vascular endothelial ROCK2 were resistant to adipose tissue expansion and insulin resistance in a high-fat diet-induced obese model. In these mice, heat production and food intake were greater after an overnight fast. Genetic analysis of adipose tissue and proteome analysis of conditioned medium obtained from ROCK2-deficient endothelium demonstrated that ROCK2 is an essential regulator of adipocyte browning. An important mechanism by which ROCK2 mediates adipocyte phenotype shifting is via the regulation of macrophage polarization. In particular, ROCK2 serves as a inducer of tumor necrosis factor α, which rewires adipose tissue-resident macrophage towards M2 phenotype. Conclusion: This study establishes endothelial ROCK2 as a key regulator of adipose tissue function and implicates ROCK2 as a novel modulator of obesity progression. Disclosure S. Ohashi: None. K. Matoba: None. K. Sekiguchi: None. E. Mitsuyoshi: None. Y. Nagai: None. R. Nishimura: Speaker's Bureau; Abbott. Advisory Panel; Abbott Japan Co., Ltd. Speaker's Bureau; Boehringer-Ingelheim, Mitsubishi Tanabe Pharma Corporation, Kowa Company, Ltd., Medtronic, Sanofi, Taiho Pharmaceutical Co. Ltd., Sumitomo Dainippon Pharma Co., Ltd., Teijin Pharma Limited, Eli Lilly and Company, Novo Nordisk A/S. Consultant; Terumo Corporation.
Ohashi et al. (Fri,) studied this question.