High-fat diet-induced obesity and insulin resistance in CYP4a14(-/-) mice is mediated by 20-HETE

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.