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.