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

We previously demonstrated that low biosynthesis of ω-3 derived pro-resolution mediators termed protectins is associated with an impaired global resolution capacity, inflammation and insulin resistance in obese high fat-fed mice(1). These findings prompted a more direct study of the therapeutic potential of protectins for the treatment of metabolic disorders. Herein we found that protectin DX (PDX) exerts an unanticipated glucoregulatory activity that is distinct from its anti-inflammatory actions. PDX was found to selectively stimulate the release of the prototypic myokine interleukin-6 (IL-6) from skeletal muscle and thereby initiate a myokine-liver signaling axis, which blunts 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 IL-6 null mice. PDX also activates AMP-activated protein kinase (AMPK) but in an IL-6 independent manner. Notably, we demonstrate that administration of PDX to obese diabetic db/db mice raises skeletal muscle IL-6 and substantially improves insulin sensitivity in this severe model of diabetes, 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.