Fat-specific DsbA-L overexpression promotes adiponectin multimerization and protects mice from diet-induced obesity and insulin resistance.
Fat-specific DsbA-L overexpression promotes adiponectin multimerization and protects mice from diet-induced obesity and insulin resistance.
复制标题
作者：
Liu M;Xiang R;Wilk SA;Zhang N;Sloane LB;Azarnoush K;Zhou L;Chen H;Xiang G;Walter CA;Austad SN;Musi N;DeFronzo RA;Asmis R;Scherer PE;Dong LQ;Liu F
脂联素的抗糖尿病和抗动脉粥样硬化作用使其成为治疗代谢和心血管疾病的理想药物靶点。然而，脂联素为基础的药物开发方法，原来是困难的，由于这种脂肪因子的血清水平极高。另一方面，脂联素多聚化与其胰岛素增敏作用之间的显著相关性已被证明，这表明一种有前途的替代治疗策略。在这里，我们表明，过表达脂肪中二硫键A氧化还原酶样蛋白（fDsbA-L）的转基因小鼠与野生型（WT）同窝仔相比，脂联素的总水平和高分子量形式增加。与WT对照小鼠相比，fDsbA-L小鼠还显示出对饮食诱导的肥胖、胰岛素抵抗和肝脂肪变性的抵抗。在脂联素缺乏的fDsbA-L小鼠（fDsbA-L/Ad−/−）中，DsbA-L过表达对饮食诱导的胰岛素抵抗的保护作用显著降低，但体重和脂肪细胞大小并未增加。此外，与高脂饮食下的脂联素敲除小鼠相比，fDsbA-L/Ad−/−小鼠表现出更大的活动和能量消耗。综上所述，我们的研究结果表明，DsbA-L通过脂联素依赖性和非依赖性机制保护小鼠免受饮食诱导的肥胖和胰岛素抵抗。此外，上调DsbA-L可能是治疗肥胖及其相关代谢紊乱的有效治疗方法。
The antidiabetic and antiatherosclerotic effects of adiponectin make it a desirable drug target for the treatment of metabolic and cardiovascular diseases. However, the adiponectin-based drug development approach turns out to be difficult due to extremely high serum levels of this adipokine. On the other hand, a significant correlation between adiponectin multimerization and its insulin-sensitizing effects has been demonstrated, suggesting a promising alternative therapeutic strategy. Here we show that transgenic mice overexpressing disulfide bond A oxidoreductase-like protein in fat (fDsbA-L) exhibited increased levels of total and the high-molecular-weight form of adiponectin compared with wild-type (WT) littermates. The fDsbA-L mice also displayed resistance to diet-induced obesity, insulin resistance, and hepatic steatosis compared with WT control mice. The protective effects of DsbA-L overexpression on diet-induced insulin resistance, but not increased body weight and fat cell size, were significantly decreased in adiponectin-deficient fDsbA-L mice (fDsbA-L/Ad−/−). In addition, the fDsbA-L/Ad−/− mice displayed greater activity and energy expenditure compared with adiponectin knockout mice under a high-fat diet. Taken together, our results demonstrate that DsbA-L protects mice from diet-induced obesity and insulin resistance through adiponectin-dependent and independent mechanisms. In addition, upregulation of DsbA-L could be an effective therapeutic approach for the treatment of obesity and its associated metabolic disorders.
登录
查看更多内容
影响因子：
5.8
作者：
Araki, Shunsuke;Dobashi, Kazushige;Shirahata, Akira
通讯作者：
Shirahata, Akira
影响因子：
8.7
作者：
Hotta, K;Funahashi, T;Matsuzawa, Y
通讯作者：
Matsuzawa, Y
DOI：
10.1093/gerona/63.5.447
发表时间：
2008-05-01
影响因子：
5.1
作者：
Atzmon, Gil;Pollin, Toni I.;Barzilai, Nir
通讯作者：
Barzilai, Nir
影响因子：
5.5
作者：
Lee, Joo-Young;Takahashi, Nobuyuki;Kawada, Teruo
通讯作者：
Kawada, Teruo
影响因子：
6.9
作者：
Ahima, Rexford S.
通讯作者：
Ahima, Rexford S.