31 Neschen, S. Morino, K. Dong, J. Wang-Fischer, Y. Cline, G. W. Romanelli, A. J. Rossbacher, J. C. Moore, I. K. Regittnig, W. Munoz, D. S. Kim, J. H. Shulman, G. I. 2007 Diabetes 56 4 1034-41 Apr 0012-1797 (Print) 17251275 Triglycerides/metabolism Reverse Transcriptase Polymerase Chain Reaction PPAR alpha/deficiency/drug effects/*genetics Mice, Knockout Mice Male Insulin Resistance Insulin/*pharmacology Glucose Clamp Technique Gene Expression Regulation/drug effects Fatty Acids, Omega-3/*pharmacology Diglycerides/metabolism Animals Acyl Coenzyme A/metabolism Knockout Fatty Acids Omega-3/*pharmacology 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. R01 DK-40936/DK/NIDDK NIH HHS/United StatesU24 DK-59635/DK/NIDDK NIH HHS/United StatesJournal ArticleResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov'tUnited States http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17251275