n-3 Fatty Acids Preserve Insulin Sensitivity In Vivo in a Peroxisome Proliferator–Activated Receptor-α–Dependent Manner

Author:

Neschen Susanne12,Morino Katsutaro12,Dong Jianying1,Wang-Fischer Yanlin1,Cline Gary W.1,Romanelli Anthony J.1,Rossbacher Jörg C.3,Moore Irene K.2,Regittnig Werner2,Munoz David S.2,Kim Jung H.4,Shulman Gerald I.124

Affiliation:

1. Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut

2. Departments of Internal Medicine, Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut

3. Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut

4. Department of Pathology, Yale University School of Medicine, New Haven, Connecticut

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)-α activation and a subsequent decrease in intracellular lipid abundance. To directly test this hypothesis, we fed PPAR-α 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-α null mice failed to counteract hepatic insulin resistance (HGP, P = NS vs. PPAR-α null safflower oil–fed mice). In PPAR-α 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-α–and diacylglycerol-dependent manner.

Publisher

American Diabetes Association

Subject

Endocrinology, Diabetes and Metabolism,Internal Medicine

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