title: Protectin DX alleviates insulin resistance by activating a myokine-liver glucoregulatory axis.
abstract: We previously demonstrated that low biosynthesis of ω-3 fatty acid-derived proresolution mediators, termed protectins, is associated with an impaired global resolution capacity, inflammation and insulin resistance in obese high-fat diet-fed mice. These findings prompted a more direct study of the therapeutic potential of protectins for the treatment of metabolic disorders. Herein we show that protectin DX (PDX) exerts an unanticipated glucoregulatory activity that is distinct from its anti-inflammatory actions. We found that PDX selectively stimulated the release of the prototypic myokine interleukin-6 (IL-6) from skeletal muscle and thereby initiated a myokine-liver signaling axis, which blunted hepatic glucose production via signal transducer and activator of transcription 3 (STAT3)-mediated transcriptional suppression of the gluconeogenic program. These effects of PDX were abrogated in Il6-null mice. PDX also activated AMP-activated protein kinase (AMPK); however, it did so in an IL-6-independent manner. Notably, we demonstrated that administration of PDX to obese diabetic db/db mice raises skeletal muscle IL-6 levels and substantially improves their insulin sensitivity without any impact on adipose tissue inflammation. Our findings thus support the development of PDX-based selective muscle IL-6 secretagogues as a new class of therapy for the treatment of insulin resistance and type 2 diabetes.
authors.affiliation: 1] Department of Medicine, Québec Heart and Lung Institute, Laval University, Québec, Québec, Canada. [2] Institute of Nutrition and Functional Foods, Laval University, Québec, Québec, Canada.
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: White
authors.affiliation: 1] Department of Medicine, Québec Heart and Lung Institute, Laval University, Québec, Québec, Canada. [2] Institute of Nutrition and Functional Foods, Laval University, Québec, Québec, Canada.
authors.forename: Philippe
authors.initials: P
authors.lastname: St-Pierre
authors.affiliation: 1] Department of Medicine, Québec Heart and Lung Institute, Laval University, Québec, Québec, Canada. [2] Institute of Nutrition and Functional Foods, Laval University, Québec, Québec, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Charbonneau
authors.affiliation: 1] Department of Medicine, Québec Heart and Lung Institute, Laval University, Québec, Québec, Canada. [2] Institute of Nutrition and Functional Foods, Laval University, Québec, Québec, Canada.
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Mitchell
authors.affiliation: 1] Department of Medicine, Québec Heart and Lung Institute, Laval University, Québec, Québec, Canada. [2] Institute of Nutrition and Functional Foods, Laval University, Québec, Québec, Canada.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: St-Amand
authors.affiliation: 1] Department of Medicine, Québec Heart and Lung Institute, Laval University, Québec, Québec, Canada. [2] Institute of Nutrition and Functional Foods, Laval University, Québec, Québec, Canada.
authors.forename: Bruno
authors.initials: B
authors.lastname: Marcotte
authors.affiliation: 1] Department of Medicine, Québec Heart and Lung Institute, Laval University, Québec, Québec, Canada. [2] Institute of Nutrition and Functional Foods, Laval University, Québec, Québec, Canada.
authors.forename: André
authors.initials: A
authors.lastname: Marette
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D000431:Ethanol / Q000008:administration & dosage; D015309:Glucose Clamp Technique; D007333:Insulin Resistance / Q000502:physiology*; D015850:Interleukin-6 / Q000378:metabolism*; D008055:Lipids / Q000008:administration & dosage; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: C000591716:10,17-dihydroxydocosa-4,7,11,13,15,19-hexaenoic acid; D015850:Interleukin-6; D008055:Lipids; D004281:Docosahexaenoic Acids; D000431:Ethanol