High-fat diet-induced obesity and insulin resistance in CYP4a14-/- mice is mediated by 20-HETE. Academic Article uri icon

Overview

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 ± 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.

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
  • Laniado Schwartzman, Michal

publication date

  • August 8, 2018

Research

keywords

  • Diet, High-Fat
  • Hydroxyeicosatetraenoic Acids
  • Insulin Resistance
  • Obesity

Identity

PubMed Central ID

  • PMC6295494

Scopus Document Identifier

  • 85055971898

Digital Object Identifier (DOI)

  • 10.1016/j.pharmthera.2009.12.002

PubMed ID

  • 30088983

Additional Document Info

volume

  • 315

issue

  • 5