n-3 Fatty acids preserve insulin sensitivity in vivo in a peroxisome proliferator-activated receptor-alpha-dependent manner.
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.
Neschen
Susanne
S
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.
Morino
Katsutaro
K
Dong
Jianying
J
Wang-Fischer
Yanlin
Y
Cline
Gary W
GW
Romanelli
Anthony J
AJ
Rossbacher
Jörg C
JC
Moore
Irene K
IK
Regittnig
Werner
W
Munoz
David S
DS
Kim
Jung H
JH
Shulman
Gerald I
GI
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
D000214:Acyl Coenzyme A; D004075:Diglycerides; D015525:Fatty Acids, Omega-3; D007328:Insulin; D047493:PPAR alpha; D014280:Triglycerides