High-fat diet-induced obesity and insulin resistance in CYP4a14-/- mice is mediated by 20-HETE
High-fat diet-induced obesity and insulin resistance in CYP4a14-/- mice is mediated by 20-HETE
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DOI：
10.1152/ajpregu.00125.2018
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发表时间：
2018-11-01
影响因子：
2.8
通讯作者：
Schwartzman, Michal Laniado
中科院分区：
文献类型：
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作者：
Gilani, Ankit;Pandey, Varunkumar;Schwartzman, Michal Laniado
20-羟基二十碳四烯酸（20-HETE）已被证明与体重指数、高血糖和血浆胰岛素水平呈正相关。本研究旨在确定20-METE与肥胖驱动的胰岛素抵抗之间的因果关系。Cyp4a14（-/-）雄性小鼠，20-HETE过量生产模型，喂食常规或高脂饮食（HFD） 15周。20-HETE拮抗剂20-SOIL [2,5,8,11,14,17 -hexaoxanonadec -19-yl - 20- hydroxyyeicsa -6 (Z),15(Z)-dienoate]从HFD的第0周或第7周开始施用。饲喂hfd的小鼠体重显著增加（16.7 +/- 3.2比3.8 +/- 0.35 g）。P < 0.05)，并发高血糖（157 +/- 3 vs. 121 +/- 7 mg/dl）。P < 0.05)和高胰岛素血症（2.3 +/- 0.4比0.5 +/- 0.1 ng/ml, P < 0.05）。20-SOLA减轻了hfd引起的体重增加（9.4 +/- 1 vs. 16.7 +/- 3 g, P < 0.05），并使高血糖（157 +/- 7 vs. 102 +/- 5 mg/dl, P < 0.05）和高胰岛素血症（1.1 +/- 0.1 vs. 2.3 +/- 0.4 ng/ml, P < 0.05）正常化。20-SOLA也改善了hfd喂养小鼠的葡萄糖稳态受损和胰岛素抵抗，证明胰岛素和葡萄糖耐量降低。hfd喂养小鼠的循环和脂肪组织20-HETE水平显著升高，这与胰岛素信号通路受损相关，包括胰岛素受体酪氨酸（Y972）磷酸化减少和胰岛素受体底物-1 （IRS-1）丝氨酸（S307）磷酸化增加。sola治疗可防止胰岛素信号的改变。这些发现表明，20-HETE有助于hfd诱导的肥胖、胰岛素抵抗和胰岛素信号受损。
20-Hydroxyeicosatetraenoic acid (20-HETE) has been shown to positively correlate with body mass index, hyperglycemia, and plasma insulin levels. This study seeks to identify a causal relationship between 20-METE and obesity-driven insulin resistance. Cyp4a14(-/-) male mice, a model of 20-HETE overproduction, were fed a regular or high-fat diet (HFD) for 15 wk. 20-SOIL [2,5,8, 11,14,17-hexaoxanonadec an-19-yl 20-hydroxyeicosa-6 (Z),15(Z)-dienoate], a 20-HETE antagonist, was administered from week 0 or week 7 of HFD. HFD-fed mice gained significant weight (16.7 +/- 3.2 vs. 3.8 +/- 0.35 g. P < 0.05) and developed hyperglycemia (157 +/- 3 vs. 121 +/- 7 mg/dl. P < 0.05) and hyperinsulinemia (2.3 +/- 0.4 vs. 0.5 +/- 0.1 ng/ml, P < 0.05) compared with regular diet-fed mice. 20-SOLA attenuated HFD-induced weight gain (9.4 +/- 1 vs. 16.7 +/- 3 g, P < 0.05) and normalized the hyperglycemia (157 +/- 7 vs. 102 +/- 5 mg/dl, P < 0.05) and hyperinsulinemia (1.1 +/- 0.1 vs. 2.3 +/- 0.4 ng/ml, P < 0.05). The impaired glucose homeostasis and insulin resistance in HFD-fed mice evidenced by reduced insulin and glucose tolerance were also ameliorated by 20-SOLA. Circulatory and adipose tissue 20-HETE levels significantly increased in HFD-fed mice correlating with impaired insulin signaling, including reduction in insulin receptor tyrosine (Y972) phosphorylation and increased serine (S307) phosphorylation of the insulin receptor substrate-1 (IRS-1). 20-SOLA treatments prevented changes in insulin signaling. These findings indicate that 20-HETE contributes to HFD-induced obesity, insulin resistance, and impaired insulin signaling.