PT - JOURNAL ARTICLE AU - Hara, Yoshikazu AU - Wakino, Shu AU - Tanabe, Yoshiyuki AU - Saito, Maki AU - Tokuyama, Hirobumi AU - Washida, Naoki AU - Tatematsu, Satoru AU - Yoshioka, Kyoko AU - Homma, Koichiro AU - Hasegawa, Kazuhiro AU - Minakuchi, Hitoshi AU - Fujimura, Keiko AU - Hosoya, Koji AU - Hayashi, Koichi AU - Nakayama, Koichi AU - Itoh, Hiroshi TI - Rho and Rho-Kinase Activity in Adipocytes Contributes to a Vicious Cycle in Obesity That May Involve Mechanical Stretch AID - 10.1126/scisignal.2001227 DP - 2011 Jan 25 TA - Science Signaling PG - ra3--ra3 VI - 4 IP - 157 4099 - http://stke.sciencemag.org/content/4/157/ra3.short 4100 - http://stke.sciencemag.org/content/4/157/ra3.full SO - Sci. Signal.2011 Jan 25; 4 AB - The development of obesity involves multiple mechanisms. Here, we identify adipocyte signaling through the guanosine triphosphatase Rho and its effector Rho-kinase as one such mechanism. Mice fed a high-fat diet (HFD) showed increased Rho-kinase activity in adipose tissue compared to mice fed a low-fat diet. Treatment with the Rho-kinase inhibitor fasudil attenuated weight gain and insulin resistance in mice on a HFD. Transgenic mice overexpressing an adipocyte-specific, dominant-negative form of RhoA (DN-RhoA TG mice) showed decreased Rho-kinase activity in adipocytes, decreased HFD-induced weight gain, and improved glucose metabolism compared to wild-type littermates. Furthermore, compared to HFD-fed wild-type littermates, DN-RhoA TG mice on a HFD showed decreased adipocyte hypertrophy, reduced macrophage recruitment to adipose tissue, and lower expression of mRNAs encoding various adipocytokines. Lipid accumulation in cultured adipocytes was associated with increased Rho-kinase activity and increased abundance of adipocytokine transcripts, which was reversed by a Rho-kinase inhibitor. Direct application of mechanical stretch to mature adipocytes increased Rho-kinase activity and stress fiber formation. Stress fiber formation, which was also observed in adipocytes from HFD-fed mice, was prevented by Rho-kinase inhibition and in DN-RhoA TG mice. Our findings indicate that lipid accumulation in adipocytes activates Rho to Rho-kinase (Rho–Rho-kinase) signaling at least in part through mechanical stretch and implicate Rho–Rho-kinase signaling in inflammatory changes in adipose tissue in obesity. Thus, inhibition of Rho–Rho-kinase signaling may provide a therapeutic strategy for disrupting a vicious cycle of adipocyte stretch, Rho–Rho-kinase signaling, and inflammation of adipose tissue that contributes to and aggravates obesity.