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Protectin DX alleviates insulin resistance by activating a myokine-liver glucoregulatory axis.

Publication ,  Journal Article
White, PJ; St-Pierre, P; Charbonneau, A; Mitchell, PL; St-Amand, E; Marcotte, B; Marette, A
Published in: Nat Med
June 2014

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.

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Published In

Nat Med

DOI

EISSN

1546-170X

Publication Date

June 2014

Volume

20

Issue

6

Start / End Page

664 / 669

Location

United States

Related Subject Headings

  • Signal Transduction
  • Muscle, Skeletal
  • Mice, Inbred C57BL
  • Mice
  • Liver
  • Lipids
  • Interleukin-6
  • Insulin Resistance
  • Immunology
  • Glucose Clamp Technique
 

Citation

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Chicago
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White, P. J., St-Pierre, P., Charbonneau, A., Mitchell, P. L., St-Amand, E., Marcotte, B., & Marette, A. (2014). Protectin DX alleviates insulin resistance by activating a myokine-liver glucoregulatory axis. Nat Med, 20(6), 664–669. https://doi.org/10.1038/nm.3549
White, Phillip J., Philippe St-Pierre, Alexandre Charbonneau, Patricia L. Mitchell, Emmanuelle St-Amand, Bruno Marcotte, and André Marette. “Protectin DX alleviates insulin resistance by activating a myokine-liver glucoregulatory axis.Nat Med 20, no. 6 (June 2014): 664–69. https://doi.org/10.1038/nm.3549.
White PJ, St-Pierre P, Charbonneau A, Mitchell PL, St-Amand E, Marcotte B, et al. Protectin DX alleviates insulin resistance by activating a myokine-liver glucoregulatory axis. Nat Med. 2014 Jun;20(6):664–9.
White, Phillip J., et al. “Protectin DX alleviates insulin resistance by activating a myokine-liver glucoregulatory axis.Nat Med, vol. 20, no. 6, June 2014, pp. 664–69. Pubmed, doi:10.1038/nm.3549.
White PJ, St-Pierre P, Charbonneau A, Mitchell PL, St-Amand E, Marcotte B, Marette A. Protectin DX alleviates insulin resistance by activating a myokine-liver glucoregulatory axis. Nat Med. 2014 Jun;20(6):664–669.

Published In

Nat Med

DOI

EISSN

1546-170X

Publication Date

June 2014

Volume

20

Issue

6

Start / End Page

664 / 669

Location

United States

Related Subject Headings

  • Signal Transduction
  • Muscle, Skeletal
  • Mice, Inbred C57BL
  • Mice
  • Liver
  • Lipids
  • Interleukin-6
  • Insulin Resistance
  • Immunology
  • Glucose Clamp Technique