title: n-3 Fatty acids preserve insulin sensitivity in vivo in a peroxisome proliferator-activated receptor-alpha-dependent manner.
abstract: 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.
authors.affiliation: Yale University School of Medicine, Howard Hughes Medical Institute, Departments of Internal Medicine, The Anlyan Center, P.O. Box 9812, New Haven, CT 06536-8012, USA.
authors.forename: Susanne
authors.initials: S
authors.lastname: Neschen
authors.forename: Katsutaro
authors.initials: K
authors.lastname: Morino
authors.forename: Jianying
authors.initials: J
authors.lastname: Dong
authors.forename: Yanlin
authors.initials: Y
authors.lastname: Wang-Fischer
authors.forename: Gary W
authors.initials: GW
authors.lastname: Cline
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Romanelli
authors.forename: Jörg C
authors.initials: JC
authors.lastname: Rossbacher
authors.forename: Irene K
authors.initials: IK
authors.lastname: Moore
authors.forename: Werner
authors.initials: W
authors.lastname: Regittnig
authors.forename: David S
authors.initials: DS
authors.lastname: Munoz
authors.forename: Jung H
authors.initials: JH
authors.lastname: Kim
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism; D000818:Animals; D004075:Diglycerides / Q000378:metabolism; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D015309:Glucose Clamp Technique; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D047493:PPAR alpha / Q000172:deficiency / Q000187:drug effects / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014280:Triglycerides / Q000378:metabolism
chemical_list: D000214:Acyl Coenzyme A; D004075:Diglycerides; D015525:Fatty Acids, Omega-3; D007328:Insulin; D047493:PPAR alpha; D014280:Triglycerides