Selective ROCK2 inhibition concurrently restores metabolic dysfunction and immune homeostasis by directly acting on both adipocytes and immune cells 9021

Abstract Description Chronic inflammation plays a major role in driving the pathogenesis of metabolic dysfunctions. Rho-associated coiled-coil kinase (ROCK)2 promotes pro-inflammatory immune responses in animal models and patients. Here we show that selective ROCK2 inhibitors regulate adipocytes functions by down-regulation of adipocyte differentiation and up-regulation of AMPK phosphorylation in human primary subcutaneous pre-adipocytes and murine 3T3L1 cells. In differentiated adipocytes, ROCK2 targeting results in decreased levels of leptin while adiponectin gene expression is increased. Therapeutic administration of a selective ROCK2 inhibitor ameliorates established liver fibrosis in mice. The efficacy in vivo is associated with improved metabolic and inflammation profiles, demonstrated by decreased levels of cholesterol, leptin, liver enzymes as well as proinflammatory cytokines including IL-17 and IL-1b, whereas levels of phosphorylated AMPK are increased in liver tissues. Moreover, treatment of liver-resident innate immune Kupffer cells and PBMCs with selective ROCK2 inhibitors robustly down-regulates LPS-induced pro-inflammatory cytokine secretion, which is associated with inhibition of inflammatory STAT3, and switch from anabolic (Akt-mTOR-S6K) to catabolic AMPK signaling pathways. In summary, these data demonstrate unique ROCK2-specific mechanism of action and underscore the therapeutic potential of selective ROCK2 inhibitors for chronic metabolic disorders. Funding Sources This work was sponsored by Graviton Bioscience Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)