High-fat diet-induced obesity and insulin resistance in CYP4A14–/– mice is mediated by 20-HETE

Ankit Gilani, Varunkumar Pandey, Victor Garcia, Kevin Agostinucci, Shailendra P. Singh, Joseph Schragenheim, Lars Bellner, J R Falck, Mahesh P. Paudyal, Jorge H. Capdevila, Nader G. Abraham, Michal Laniado Schwartzman

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

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 ± 3g, 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.

Original languageEnglish (US)
Pages (from-to)R934-R944
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume315
Issue number5
DOIs
StatePublished - Nov 1 2018

Keywords

  • Hyperglycemia
  • Hyperinsulinemia
  • Insulin resistance
  • Obesity

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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    Gilani, A., Pandey, V., Garcia, V., Agostinucci, K., Singh, S. P., Schragenheim, J., Bellner, L., Falck, J. R., Paudyal, M. P., Capdevila, J. H., Abraham, N. G., & Laniado Schwartzman, M. (2018). High-fat diet-induced obesity and insulin resistance in CYP4A14–/– mice is mediated by 20-HETE. American Journal of Physiology - Regulatory Integrative and Comparative Physiology, 315(5), R934-R944. https://doi.org/10.1152/ajpregu.00125.2018