High-fat diet-induced obesity and insulin resistance in CYP4a14^sup −/−^ mice is mediated by 20-HETE

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology Vol. 315; no. 5; p. R934
• Main Authors: Gilani, Ankit, Pandey, Varunkumar, Garcia, Victor, Agostinucci, Kevin, Singh, Shailendra P, Schragenheim, Joseph, Bellner, Lars, Falck, John R, Paudyal, Mahesh P, Capdevila, Jorge H, Abraham, Nader G, Schwartzman, Michal Laniado
• Format: Journal Article
• Language: English
• Published: Bethesda American Physiological Society 01.11.2018
• Subjects: Adipose tissue; Body mass; Body mass index; Body size; Body weight gain; Diet; Glucose; Glucose tolerance; High fat diet; Homeostasis; Hyperglycemia; Hyperinsulinemia; Insulin; Insulin receptor substrate 1; Insulin resistance; Mice; Obesity; Phosphorylation; Rodents; Serine; Signaling; Substrates; Tyrosine
• ISSN: 0363-6119; 1522-1490

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-HETE 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-SOLA [2,5,8,11,14,17-hexaoxanonadecan-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.