title: Obesity-induced insulin resistance and hepatic steatosis are alleviated by omega-3 fatty acids: a role for resolvins and protectins.
abstract: Omega-3-polyunsaturated fatty acids (omega-3-PUFAs) have well-documented protective effects that are attributed not only to eicosanoid inhibition but also to the formation of novel biologically active lipid mediators (i.e., resolvins and protectins). In this study, we examined their effects on ob/ob mice, an obesity model of insulin resistance and fatty liver disease. Dietary intake of omega-3-PUFAs had insulin-sensitizing actions in adipose tissue and liver and improved insulin tolerance in obese mice. Genes involved in insulin sensitivity (PPARgamma), glucose transport (GLUT-2/GLUT-4), and insulin receptor signaling (IRS-1/IRS-2) were up-regulated by omega-3-PUFAs. Moreover, omega-3-PUFAs increased adiponectin, an anti-inflammatory and insulin-sensitizing adipokine, and induced AMPK phosphorylation, a fuel-sensing enzyme and a gatekeeper of the energy balance. Concomitantly, hepatic steatosis was alleviated by omega-3-PUFAs. A lipidomic analysis with liquid chromatography/mass spectrometry/mass spectrometry revealed that omega-3-PUFAs inhibited the formation of omega-6-PUFA-derived eicosanoids, while triggering the formation of omega-3-PUFA-derived resolvins and protectins. Moreover, representative members of these lipid mediators, namely resolvin E1 and protectin D1, mimicked the insulin-sensitizing and antisteatotic effects of omega-3-PUFAs and induced adiponectin expression to a similar extent that of rosiglitazone, a member of the thiazolidinedione family of antidiabetic drugs. Taken together, these findings uncover beneficial actions of omega-3-PUFAs and their bioactive lipid autacoids in preventing obesity-induced insulin resistance and hepatic steatosis.
authors.affiliation: Department of Biochemistry and Molecular Genetics, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi I Sunyer, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, University of Barcelona, Barcelona, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: González-Périz
authors.forename: Raquel
authors.initials: R
authors.lastname: Horrillo
authors.forename: Natàlia
authors.initials: N
authors.lastname: Ferré
authors.forename: Karsten
authors.initials: K
authors.lastname: Gronert
authors.forename: Baiyan
authors.initials: B
authors.lastname: Dong
authors.forename: Eva
authors.initials: E
authors.lastname: Morán-Salvador
authors.forename: Esther
authors.initials: E
authors.lastname: Titos
authors.forename: Marcos
authors.initials: M
authors.lastname: Martínez-Clemente
authors.forename: Marta
authors.initials: M
authors.lastname: López-Parra
authors.forename: Vicente
authors.initials: V
authors.lastname: Arroyo
authors.forename: Joan
authors.initials: J
authors.lastname: Clària
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D052242:Adiponectin / Q000235:genetics / Q000378:metabolism; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism; D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D004032:Diet; D004041:Dietary Fats / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D015118:Eicosapentaenoic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D015525:Fatty Acids, Omega-3 / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D005234:Fatty Liver / Q000178:diet therapy* / Q000378:metabolism* / Q000473:pathology; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008820:Mice, Obese; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity / Q000378:metabolism / Q000473:pathology; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D052243:Resistin / Q000235:genetics / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000378:metabolism
chemical_list: D052242:Adiponectin; D018932:Chemokine CCL2; D004041:Dietary Fats; D015525:Fatty Acids, Omega-3; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D047495:PPAR gamma; D052243:Resistin; C495693:Slc2a4 protein, mouse; D045162:Thiazolidinediones; C487679:protectin D1; D000077154:Rosiglitazone; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid; D055372:AMP-Activated Protein Kinases; C499823:5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid