Endothelium-specific CYP2J2 overexpression attenuates age-related insulin resistance.
Endothelium-specific CYP2J2 overexpression attenuates age-related insulin resistance.
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作者：
Yang Y;Dong R;Chen Z;Hu D;Fu M;Tang Y;Wang DW;Xu X;Tu L
大量证据表明，细胞色素P450环氧合酶衍生的环氧二十碳三烯酸（Epoxyeicosatrienoic Acids，ESTs）具有多种生物活性，包括有效的血管扩张，抗炎和心血管保护作用。在这项研究中，我们研究了内皮特异性CYP 2 J2过表达对年龄相关的胰岛素抵抗和代谢功能障碍的影响。利用人β-环氧合酶CYP 2 J2转基因小鼠（Tie 2-CYP 2 J2-Tr小鼠）的内皮素特异性靶向。通过评估年轻（3月龄）和老年（16月龄）成年雄性Tie 2-CYP 2 J2-Tr小鼠的代谢参数，评价了内皮特异性CYP 2 J2过表达对衰老相关肥胖、炎症和外周胰岛素抵抗的影响。在老年成年雄性小鼠中观察到老年骨骼肌、脂肪组织和肝脏中的胰岛素敏感性降低和胰岛素信号转导减弱，此外，这些作用在16个月龄的CYP 2 J2 ‐Tr小鼠中部分抑制。此外，老年小鼠中CYP 2 J2过表达介导的胰岛素增敏与炎症状态的改善相关。值得注意的是，仅在16个月大的野生型小鼠中观察到脂肪量和脂肪细胞大小的衰老相关增加，CYP 2 J2过表达显著阻止了老年Tie 2-CYP 2 J2-Tr小鼠的脂肪量和脂肪细胞大小的增加，这与能量消耗增加和脂肪生成基因表达减少有关。此外，Tie 2-CYP 2 J2-Tr小鼠的这些抗衰老表型还与肌血流量增加、活跃期运动活动增强和骨骼肌线粒体功能障碍改善相关。总的来说，我们的研究结果表明，内皮特异性CYP 2 J2过表达减轻了与年龄相关的胰岛素抵抗和代谢功能障碍，这突出了EET系统作为对抗衰老相关代谢紊乱的潜在靶点。
Ample evidences demonstrate that cytochrome P450 epoxygenase‐derived epoxyeicosatrienoic acids (EETs) exert diverse biological activities, which include potent vasodilatory, anti‐inflammatory, and cardiovascular protective effects. In this study, we investigated the effects of endothelium‐specific CYP2J2 overexpression on age‐related insulin resistance and metabolic dysfunction. Endothelium‐specific targeting of the human CYP epoxygenase, CYP2J2, transgenic mice (Tie2‐CYP2J2‐Tr mice) was utilized. The effects of endothelium‐specific CYP2J2 overexpression on aging‐associated obesity, inflammation, and peripheral insulin resistance were evaluated by assessing metabolic parameters in young (3 months old) and aged (16 months old) adult male Tie2‐CYP2J2‐Tr mice. Decreased insulin sensitivity and attenuated insulin signaling in aged skeletal muscle, adipose tissue, and liver were observed in aged adult male mice, and moreover, these effects were partly inhibited in 16‐month‐old CYP2J2‐Tr mice. In addition, CYP2J2 overexpression‐mediated insulin sensitization in aged mice was associated with the amelioration of inflammatory state. Notably, the aging‐associated increases in fat mass and adipocyte size were only observed in 16‐month‐old wild‐type mice, and CYP2J2 overexpression markedly prevented the increase in fat mass and adipocyte size in aged Tie2‐CYP2J2‐Tr mice, which was associated with increased energy expenditure and decreased lipogenic genes expression. Furthermore, these antiaging phenotypes of Tie2‐CYP2J2‐Tr mice were also associated with increased muscle blood flow, enhanced active‐phase locomotor activity, and improved mitochondrial dysfunction in skeletal muscle. Collectively, our findings indicated that endothelium‐specific CYP2J2 overexpression alleviated age‐related insulin resistance and metabolic dysfunction, which highlighted CYP epoxygenase‐EET system as a potential target for combating aging‐related metabolic disorders.
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影响因子：
7.8
作者：
Akasaki Y;Ouchi N;Izumiya Y;Bernardo BL;Lebrasseur NK;Walsh K
通讯作者：
Walsh K
影响因子：
3.9
作者：
Palmer, Allyson K.;Kirkland, James L.
通讯作者：
Kirkland, James L.
DOI：
10.1161/hypertensionaha.114.03884
发表时间：
2014-12
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
Abraham NG;Sodhi K;Silvis AM;Vanella L;Favero G;Rezzani R;Lee C;Zeldin DC;Schwartzman ML
通讯作者：
Schwartzman ML
DOI：
10.1124/jpet.111.180505
发表时间：
2011-11-01
影响因子：
3.5
作者：
Liu, Liu;Chen, Chen;Wang, Dao Wen
通讯作者：
Wang, Dao Wen
影响因子：
7.3
作者：
Batchu, S. N.;Lee, S. B.;Seubert, J. M.
通讯作者：
Seubert, J. M.