Rho and Rho-Kinase Activity in Adipocytes Contributes to a Vicious Cycle in Obesity That May Involve Mechanical Stretch
Rho and Rho-Kinase Activity in Adipocytes Contributes to a Vicious Cycle in Obesity That May Involve Mechanical Stretch
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DOI：
10.1126/scisignal.2001227
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发表时间：
2011-01-25
影响因子：
7.3
通讯作者：
Itoh, Hiroshi
中科院分区：
文献类型：
--
作者：
Hara, Yoshikazu;Wakino, Shu;Itoh, Hiroshi
肥胖的发生涉及多种机制。在这里，我们确定脂肪细胞信号通过鸟苷三磷酸酶Rho和其效应Rho激酶作为这样的机制之一。与喂食低脂饮食的小鼠相比，喂食高脂饮食（HFD）的小鼠脂肪组织中的Rho激酶活性增加。Rho激酶抑制剂法舒地尔治疗可减轻HFD小鼠的体重增加和胰岛素抵抗。过表达脂肪细胞特异性显性负性RhoA的转基因小鼠（DN-RhoA TG小鼠）与野生型同窝仔相比，脂肪细胞中Rho激酶活性降低，HFD诱导的体重增加减少，葡萄糖代谢改善。此外，与HFD喂养的野生型同窝小鼠相比，HFD喂养的DN-RhoA TG小鼠显示脂肪细胞肥大减少，巨噬细胞向脂肪组织的募集减少，以及编码各种脂肪细胞因子的mRNA表达降低。培养的脂肪细胞中的脂质积累与Rho激酶活性增加和脂肪细胞因子转录物丰度增加相关，这可被Rho激酶抑制剂逆转。直接应用机械拉伸成熟脂肪细胞增加Rho激酶活性和应力纤维形成。在HFD喂养小鼠的脂肪细胞中也观察到的应力纤维形成通过Rho激酶抑制和DN-RhoA TG小鼠中被阻止。我们的研究结果表明，脂肪细胞中的脂质积累至少部分地通过机械拉伸激活Rho至Rho激酶（Rho-Rho-kinase）信号传导，并且在肥胖症中脂肪组织的炎症变化中涉及Rho-Rho-kinase信号传导。因此，Rho-Rho-激酶信号传导的抑制可以提供用于破坏脂肪细胞拉伸、Rho-Rho-激酶信号传导和脂肪组织炎症的恶性循环的治疗策略，所述脂肪组织炎症促成和加重肥胖。
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.