20-HETE interferes with insulin signaling and contributes to obesity-driven insulin resistance

Prostaglandins Other Lipid Mediat. 2021 Feb:152:106485. doi: 10.1016/j.prostaglandins.2020.106485. Epub 2020 Oct 1.

Abstract

20-HETE, a metabolite of arachidonic acid produced by Cytochrome P450 (CYP) 4A/4 F, has been implicated in the development of obesity-associated complications such as diabetes and insulin resistance. In this study, we examined whether the acute elevation of 20-HETE levels contributes to the development of diet-driven hyperglycemia and insulin resistance. We employed a conditional transgenic mouse model to overexpress Cyp4a12 (Cyp4a12tg), a murine 20-HETE synthase, together with high fat diet (HFD) feeding. Mice in which Cyp4a12 was induced by doxycycline (DOX) at the onset of HFD feeding gained weight at a greater rate and extent than corresponding DOX-untreated Cyp4a12 mice. Cyp4a12tg mice fed HFD + DOX displayed hyperglycemia and impaired glucose metabolism while corresponding HFD-fed Cyp4a12tg mice (no DOX) did not. Importantly, administration of a 20-HETE antagonist, 20-SOLA, to Cyp4a12tg mice fed HFD + DOX significantly attenuated weight gain and prevented the development of hyperglycemia and impaired glucose metabolism. Levels of insulin receptor (IR) phosphorylation at Tyrosine 972 and insulin receptor substrate-1 (IRS1) phosphorylation at serine 307 were markedly decreased and increased, respectively, in liver, skeletal muscle and adipose tissues from Cyp4a12tg mice fed HFD + DOX; 20-SOLA prevented the IR and IRS1 inactivation, suggesting that 20-HETE interferes with insulin signaling. Additional studies in 3T3-1 differentiated adipocytes confirmed that 20-HETE impairs insulin signaling and that its effect may require activation of its receptor GPR75. Taken together, these results provide strong evidence that 20-HETE interferes with insulin function and contributed to diet-driven insulin resistance.

Keywords: 20-HETE; GPR75; High-fat diet; Hyperglycemia; Insulin resistance.

MeSH terms

  • Animals
  • Diet, High-Fat* / adverse effects
  • Hydroxyeicosatetraenoic Acids* / metabolism
  • Insulin Resistance*
  • Insulin* / metabolism
  • Male
  • Mice
  • Mice, Transgenic*
  • Obesity* / metabolism
  • Signal Transduction* / drug effects

Substances

  • 20-hydroxy-5,8,11,14-eicosatetraenoic acid
  • Hydroxyeicosatetraenoic Acids
  • Insulin