Department of Geriatric Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Hubei Key laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders and Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Aging Cell. 2018 Apr;17(2). doi: 10.1111/acel.12718. Epub 2018 Jan 10.
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.
大量证据表明细胞色素 P450 加单氧酶衍生的环氧二十碳三烯酸（EETs）具有多种生物学活性，包括强效的血管舒张、抗炎和心血管保护作用。在这项研究中，我们研究了内皮细胞特异性 CYP2J2 过表达对与年龄相关的胰岛素抵抗和代谢功能障碍的影响。利用内皮细胞特异性靶向人类 CYP 加单氧酶 CYP2J2 的转基因小鼠（Tie2-CYP2J2-Tr 小鼠）。通过评估年轻（3 个月大）和年老（16 个月大）成年雄性 Tie2-CYP2J2-Tr 小鼠的代谢参数，评估内皮细胞特异性 CYP2J2 过表达对与年龄相关的肥胖、炎症和外周胰岛素抵抗的影响。在年老的成年雄性小鼠中观察到骨骼肌、脂肪组织和肝脏中胰岛素敏感性降低和胰岛素信号减弱，而且这些影响在 16 个月大的 CYP2J2-Tr 小鼠中部分受到抑制。此外，CYP2J2 过表达介导的年老小鼠胰岛素敏感性增加与炎症状态的改善有关。值得注意的是，只有在 16 个月大的野生型小鼠中才观察到与年龄相关的脂肪量增加和脂肪细胞增大，而 CYP2J2 过表达显著防止了年老的 Tie2-CYP2J2-Tr 小鼠中脂肪量和脂肪细胞增大，这与能量消耗增加和脂肪生成基因表达减少有关。此外，Tie2-CYP2J2-Tr 小鼠的这些抗衰老表型也与肌肉血流增加、活跃相运动活性增强和骨骼肌线粒体功能障碍改善有关。总之，我们的研究结果表明，内皮细胞特异性 CYP2J2 过表达减轻了与年龄相关的胰岛素抵抗和代谢功能障碍，这突显了 CYP 加单氧酶-EET 系统作为治疗与年龄相关的代谢紊乱的潜在靶点。
