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Sci. Signal., 25 January 2011
Vol. 4, Issue 157, p. ra3
[DOI: 10.1126/scisignal.2001227]

RESEARCH ARTICLES

Rho and Rho-Kinase Activity in Adipocytes Contributes to a Vicious Cycle in Obesity That May Involve Mechanical Stretch

Yoshikazu Hara1, Shu Wakino1*, Yoshiyuki Tanabe2, Maki Saito2, Hirobumi Tokuyama1, Naoki Washida1, Satoru Tatematsu1, Kyoko Yoshioka1, Koichiro Homma1, Kazuhiro Hasegawa1, Hitoshi Minakuchi1, Keiko Fujimura1, Koji Hosoya1, Koichi Hayashi1, Koichi Nakayama2, and Hiroshi Itoh1

1 Department of Internal Medicine, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan.
2 Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Iwate Medical University, Iwate 028-3694, Japan.

Abstract: 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.

* To whom correspondence should be addressed. E-mail: swakino{at}sc.itc.keio.ac.jp

Citation: Y. Hara, S. Wakino, Y. Tanabe, M. Saito, H. Tokuyama, N. Washida, S. Tatematsu, K. Yoshioka, K. Homma, K. Hasegawa, H. Minakuchi, K. Fujimura, K. Hosoya, K. Hayashi, K. Nakayama, H. Itoh, Rho and Rho-Kinase Activity in Adipocytes Contributes to a Vicious Cycle in Obesity That May Involve Mechanical Stretch. Sci. Signal. 4, ra3 (2011).

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