20-HETE, a metabolite of arachidonic acid produced by Cytochrome P450 (CYP) 4A/4 F, has been implicated in the development of obesity-associated complications such as diabetes and insulin resistance. In this study, we examined whether the acute elevation of 20-HETE levels contributes to the development of diet-driven hyperglycemia and insulin resistance. We employed a conditional transgenic mouse model to overexpress Cyp4a12 (Cyp4a12tg), a murine 20-HETE synthase, together with high fat diet (HFD) feeding. Mice in which Cyp4a12 was induced by doxycycline (DOX) at the onset of HFD feeding gained weight at a greater rate and extent than corresponding DOX-untreated Cyp4a12 mice. Cyp4a12tg mice fed HFD + DOX displayed hyperglycemia and impaired glucose metabolism while corresponding HFD-fed Cyp4a12tg mice (no DOX) did not. Importantly, administration of a 20-HETE antagonist, 20-SOLA, to Cyp4a12tg mice fed HFD + DOX significantly attenuated weight gain and prevented the development of hyperglycemia and impaired glucose metabolism. Levels of insulin receptor (IR) phosphorylation at Tyrosine 972 and insulin receptor substrate-1 (IRS1) phosphorylation at serine 307 were markedly decreased and increased, respectively, in liver, skeletal muscle and adipose tissues from Cyp4a12tg mice fed HFD + DOX; 20-SOLA prevented the IR and IRS1 inactivation, suggesting that 20-HETE interferes with insulin signaling. Additional studies in 3T3−1 differentiated adipocytes confirmed that 20-HETE impairs insulin signaling and that its effect may require activation of its receptor GPR75. Taken together, these results provide strong evidence that 20-HETE interferes with insulin function and contributed to diet-driven insulin resistance

20-HETE 是一种由细胞色素 P450 (CYP) 4A/4 F 产生的花生四烯酸代谢物，与糖尿病和胰岛素抵抗等肥胖相关并发症的发生有关。在这项研究中，我们研究了 20-HETE 水平的急剧升高是否会导致饮食驱动的高血糖和胰岛素抵抗的发生。我们采用条件转基因小鼠模型来过度表达 Cyp4a12 (Cyp4a12tg)（一种鼠科动物 20-HETE 合酶），并辅以高脂肪饮食 (HFD) 喂养。在 HFD 喂养开始时，用多西环素 (DOX) 诱导 Cyp4a12 的小鼠体重增加的速度和程度比相应的未处理 DOX 的 Cyp4a12 小鼠要快。饲喂 HFD + DOX 的 Cyp4a12tg 小鼠表现出高血糖和葡萄糖代谢受损，而相应的 HFD 饲喂的 Cyp4a12tg 小鼠（无 DOX）则没有。重要的是，给饲喂 HFD + DOX 的 Cyp4a12tg 小鼠施用 20-HETE 拮抗剂 20-SOLA 可以显着减轻体重增加，并防止高血糖和葡萄糖代谢受损的发生。在喂食 HFD + DOX 的 Cyp4a12tg 小鼠的肝脏、骨骼肌和脂肪组织中，酪氨酸 972 处的胰岛素受体 (IR) 磷酸化水平和丝氨酸 307 处的胰岛素受体底物 -1 (IRS1) 磷酸化水平分别显着降低和升高； 20-SOLA 阻止 IR 和 IRS1 失活，表明 20-HETE 干扰胰岛素信号传导。对 3T3−1 分化脂肪细胞的其他研究证实，20-HETE 会损害胰岛素信号传导，并且其作用可能需要激活其受体 GPR75。总而言之，这些结果提供了强有力的证据，证明 20-HETE 会干扰胰岛素功能并导致饮食驱动的胰岛素抵抗