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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 mice1. 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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Figure 1: PDX prevents lipid-induced insulin resistance.
Figure 2: PDX stimulates skeletal muscle IL-6 expression.
Figure 3: IL-6 is required for the insulin-sensitizing actions of PDX.
Figure 4: PDX therapy improves insulin sensitivity in diabetic mice.

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Acknowledgements

We thank C. Dion for surgical preparation of the mice and S. Pelletier for assistance with the palmitate macrophage studies. We also thank C. Serhan (Brigham and Women's Hospital, Harvard University) and N. Flamand (Heart and Lung Institute, Laval University) for providing PD1 and (8S,15S)-diHETE, respectively, and M. Schwab and K. Bellmann for their help with the PCR analyses. T37i fibroblasts were a gift from M. Lombès, INSERM U478. This work was supported by grants to A.M. from the Canadian Diabetes Association and from the Canadian Institutes of Health Research (CIHR). A.M. is partially funded by a CIHR/Pfizer Chair in the pathogenesis of insulin resistance and cardiovascular diseases. P.J.W. is the recipient of a PhD studentship award from the Fonds de la Recherche en Santé du Quebec.

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P.J.W. and A.M. conceived of the study and wrote the manuscript. P.J.W., P.S.-P., A.C., P.L.M. and E.S.-A. performed mouse experiments. P.J.W., P.L.M., B.M. and E.S.-A. performed cell culture experiments. P.J.W., P.L.M., E.S.-A. and B.M. conducted ELISA and multiplex analyses. P.J.W. and P.L.M. carried out western blotting and PCR. All authors analyzed and discussed data and commented on the manuscript.

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Correspondence to André Marette.

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Competing interests

A.M. and P.J.W. have filed a patent application (PCT/CA2014/000047) with the Canadian Patent Office describing a method and use for the stimulation of muscular IL-6 secretion.

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White, P., St-Pierre, P., Charbonneau, A. et al. Protectin DX alleviates insulin resistance by activating a myokine-liver glucoregulatory axis. Nat Med 20, 664–669 (2014). https://doi.org/10.1038/nm.3549

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