Rho and Rho-kinase activity in adipocytes contributes to a vicious cycle in obesity that may involve mechanical stretch.
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.
Department of Internal Medicine, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan.
Yoshikazu
Y
Hara
Shu
S
Wakino
Yoshiyuki
Y
Tanabe
Maki
M
Saito
Hirobumi
H
Tokuyama
Naoki
N
Washida
Satoru
S
Tatematsu
Kyoko
K
Yoshioka
Koichiro
K
Homma
Kazuhiro
K
Hasegawa
Hitoshi
H
Minakuchi
Keiko
K
Fujimura
Koji
K
Hosoya
Koichi
K
Hayashi
Koichi
K
Nakayama
Hiroshi
H
Itoh
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D018752:Diet, Fat-Restricted; D007333:Insulin Resistance / Q000502:physiology; D055595:Mechanical Phenomena; D051379:Mice; D008822:Mice, Transgenic; D009765:Obesity / Q000378:metabolism* / Q000503:physiopathology; D010641:Phenotype; D015398:Signal Transduction / Q000502:physiology*; D015430:Weight Gain / Q000502:physiology; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; D020741:rho GTP-Binding Proteins; C049347:fasudil