n-3 Fatty acids preserve insulin sensitivity in vivo in a peroxisome proliferator-activated receptor-alpha-dependent manner

Diabetes. 2007 Apr;56(4):1034-41. doi: 10.2337/db06-1206. Epub 2007 Jan 24.


Recent studies have suggested that n-3 fatty acids, abundant in fish oil, protect against high-fat diet-induced insulin resistance through peroxisome proliferator-activated receptor (PPAR)-alpha activation and a subsequent decrease in intracellular lipid abundance. To directly test this hypothesis, we fed PPAR-alpha null and wild-type mice for 2 weeks with isocaloric high-fat diets containing 27% fat from either safflower oil or safflower oil with an 8% fish oil replacement (fish oil diet). In both genotypes the safflower oil diet blunted insulin-mediated suppression of hepatic glucose production (P < 0.02 vs. genotype control) and PEPCK gene expression. Feeding wild-type mice a fish oil diet restored hepatic insulin sensitivity (hepatic glucose production [HGP], P < 0.002 vs. wild-type mice fed safflower oil), whereas in contrast, in PPAR-alpha null mice failed to counteract hepatic insulin resistance (HGP, P = NS vs. PPAR-alpha null safflower oil-fed mice). In PPAR-alpha null mice fed the fish oil diet, safflower oil plus fish oil, hepatic insulin resistance was dissociated from increases in hepatic triacylglycerol and acyl-CoA but accompanied by a more than threefold increase in hepatic diacylglycerol concentration (P < 0.0001 vs. genotype control). These data support the hypothesis that n-3 fatty acids protect from high-fat diet-induced hepatic insulin resistance in a PPAR-alpha-and diacylglycerol-dependent manner.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyl Coenzyme A / metabolism
  • Animals
  • Diglycerides / metabolism
  • Fatty Acids, Omega-3 / pharmacology*
  • Gene Expression Regulation / drug effects
  • Glucose Clamp Technique
  • Insulin / pharmacology*
  • Insulin Resistance
  • Male
  • Mice
  • Mice, Knockout
  • PPAR alpha / deficiency
  • PPAR alpha / drug effects
  • PPAR alpha / genetics*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Triglycerides / metabolism


  • Acyl Coenzyme A
  • Diglycerides
  • Fatty Acids, Omega-3
  • Insulin
  • PPAR alpha
  • Triglycerides