Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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


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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it


Prices may be subject to local taxes which are calculated during checkout

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.


  1. White, P.J., Arita, M., Taguchi, R., Kang, J.X. & Marette, A. Transgenic restoration of long-chain n–3 fatty acids in insulin target tissues improves resolution capacity and alleviates obesity-linked inflammation and insulin resistance in high-fat–fed mice. Diabetes 59, 3066–3073 (2010).

    Article  CAS  Google Scholar 

  2. Serhan, C.N. et al. Anti-inflammatory actions of neuroprotectin D1/protectin D1 and its natural stereoisomers: assignments of dihydroxy-containing docosatrienes. J. Immunol. 176, 1848–1859 (2006).

    Article  CAS  Google Scholar 

  3. Chen, P. et al. Full characterization of PDX, a neuroprotectin/protectin D1 isomer, which inhibits blood platelet aggregation. FEBS Lett. 583, 3478–3484 (2009).

    Article  CAS  Google Scholar 

  4. Awazawa, M. et al. Adiponectin enhances insulin sensitivity by increasing hepatic IRS-2 expression via a macrophage-derived IL-6–dependent pathway. Cell Metab. 13, 401–412 (2011).

    Article  CAS  Google Scholar 

  5. Pedersen, B.K. & Febbraio, M.A. Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol. Rev. 88, 1379–1406 (2008).

    Article  CAS  Google Scholar 

  6. Pedersen, B.K. & Febbraio, M.A. Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat. Rev. Endocrinol. 8, 457–465 (2012).

    Article  CAS  Google Scholar 

  7. Stanford, K.I. et al. Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. J. Clin. Invest. 123, 215–223 (2013).

    Article  CAS  Google Scholar 

  8. Sag, D., Carling, D., Stout, R.D. & Suttles, J. Adenosine 5′-monophosphate–activated protein kinase promotes macrophage polarization to an anti-inflammatory functional phenotype. J. Immunol. 181, 8633–8641 (2008).

    Article  CAS  Google Scholar 

  9. Inoue, H. et al. Role of hepatic STAT3 in brain-insulin action on hepatic glucose production. Cell Metab. 3, 267–275 (2006).

    Article  CAS  Google Scholar 

  10. Inoue, H. et al. Role of STAT-3 in regulation of hepatic gluconeogenic genes and carbohydrate metabolism in vivo. Nat. Med. 10, 168–174 (2004).

    Article  CAS  Google Scholar 

  11. Carey, A.L. et al. Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase. Diabetes 55, 2688–2697 (2006).

    Article  CAS  Google Scholar 

  12. Kelly, M., Gauthier, M.S., Saha, A.K. & Ruderman, N.B. Activation of AMP-activated protein kinase by interleukin-6 in rat skeletal muscle: association with changes in cAMP, energy state, and endogenous fuel mobilization. Diabetes 58, 1953–1960 (2009).

    Article  CAS  Google Scholar 

  13. Kelly, M. et al. AMPK activity is diminished in tissues of IL-6 knockout mice: the effect of exercise. Biochem. Biophys. Res. Commun. 320, 449–454 (2004).

    Article  CAS  Google Scholar 

  14. Clària, J., Dalli, J., Yacoubian, S., Gao, F. & Serhan, C.N. Resolvin D1 and resolvin D2 govern local inflammatory tone in obese fat. J. Immunol. 189, 2597–2605 (2012).

    Article  Google Scholar 

  15. Jové, M., Planavila, A., Laguna, J.C. & Vázquez-Carrera, M. Palmitate-induced interleukin 6 production is mediated by protein kinase C and nuclear-factor κB activation and leads to glucose transporter 4 down-regulation in skeletal muscle cells. Endocrinology 146, 3087–3095 (2005).

    Article  Google Scholar 

  16. Shi, H. et al. TLR4 links innate immunity and fatty acid-induced insulin resistance. J. Clin. Invest. 116, 3015–3025 (2006).

    Article  CAS  Google Scholar 

  17. Wunderlich, F.T. et al. Interleukin-6 signaling in liver-parenchymal cells suppresses hepatic inflammation and improves systemic insulin action. Cell Metab. 12, 237–249 (2010).

    Article  CAS  Google Scholar 

  18. Pedersen, B.K. & Febbraio, M.A. Point: interleukin-6 does have a beneficial role in insulin sensitivity and glucose homeostasis. J. Appl. Physiol. 102, 814–816 (2007).

    Article  CAS  Google Scholar 

  19. Mauer, J. et al. Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin. Nat. Immunol. 15, 423–430 (2014).

    Article  CAS  Google Scholar 

  20. Gray, S.R., Ratkevicius, A., Wackerhage, H., Coats, P. & Nimmo, M.A. The effect of interleukin-6 and the interleukin-6 receptor on glucose transport in mouse skeletal muscle. Exp. Physiol. 94, 899–905 (2009).

    Article  CAS  Google Scholar 

  21. Tweedell, A. et al. Metabolic response to endotoxin in vivo in the conscious mouse: role of interleukin-6. Metabolism 60, 92–98 (2011).

    Article  CAS  Google Scholar 

  22. Pilon, G., Dallaire, P. & Marette, A. Inhibition of inducible nitric-oxide synthase by activators of AMP-activated protein kinase: a new mechanism of action of insulin-sensitizing drugs. J. Biol. Chem. 279, 20767–20774 (2004).

    Article  CAS  Google Scholar 

  23. Centeno-Baez, C., Dallaire, P. & Marette, A. Resveratrol inhibition of inducible nitric oxide synthase in skeletal muscle involves AMPK but not SIRT1. Am. J. Physiol. Endocrinol. Metab. 301, E922–E930 (2011).

    Article  CAS  Google Scholar 

  24. Charbonneau, A. & Marette, A. Inducible nitric oxide synthase induction underlies lipid-induced hepatic insulin resistance in mice: potential role of tyrosine nitration of insulin signaling proteins. Diabetes 59, 861–871 (2010).

    Article  CAS  Google Scholar 

  25. Xu, E. et al. Targeted disruption of carcinoembryonic antigen-related cell adhesion molecule 1 promotes diet-induced hepatic steatosis and insulin resistance. Endocrinology 150, 3503–3512 (2009).

    Article  CAS  Google Scholar 

  26. Mari, A. Estimation of the rate of appearance in the non-steady state with a two-compartment model. Am. J. Physiol. 263, E400–E415 (1992).

    CAS  PubMed  Google Scholar 

  27. Mulvihill, E.E. et al. Nobiletin attenuates VLDL overproduction, dyslipidemia, and atherosclerosis in mice with diet-induced insulin resistance. Diabetes 60, 1446–1457 (2011).

    Article  CAS  Google Scholar 

  28. Xu, E. et al. Hepatocyte-specific Ptpn6 deletion protects from obesity-linked hepatic insulin resistance. Diabetes 61, 1949–1958 (2012).

    Article  CAS  Google Scholar 

  29. Chung, J. et al. HSP72 protects against obesity-induced insulin resistance. Proc. Natl. Acad. Sci. USA 105, 1739–1744 (2008).

    Article  CAS  Google Scholar 

  30. Jenkins, Y. et al. AMPK activation through mitochondrial regulation results in increased substrate oxidation and improved metabolic parameters in models of diabetes. PLoS ONE 8, e81870 (2013).

    Article  Google Scholar 

  31. Moh, A. et al. STAT3 sensitizes insulin signaling by negatively regulating glycogen synthase kinase-3 β. Diabetes 57, 1227–1235 (2008).

    Article  CAS  Google Scholar 

  32. Río, A. et al. Reduced liver injury in the interleukin-6 knockout mice by chronic carbon tetrachloride administration. Eur. J. Clin. Invest. 38, 306–316 (2008).

    Article  Google Scholar 

  33. Schmittgen, T.D. & Livak, K.J. Analyzing real-time PCR data by the comparative CT method. Nat. Protoc. 3, 1101–1108 (2008).

    Article  CAS  Google Scholar 

Download references


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.

Author information

Authors and Affiliations



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.

Corresponding author

Correspondence to André Marette.

Ethics declarations

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.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6 (PDF 3352 kb)

Source data

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing