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

Abstract

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 mice1. 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.

Skeletal muscle glucose metabolism and inflammation in the development of the metabolic syndrome

“…We found that PDX fully prevents insulin resistance by improving insulin's metabolic action and Akt activation in skeletal muscle and liver of lipid-infused mice [64]. As anticipated, this was associated with decreased lipid-induced activation of iNOS and JNK in both tissues, and suppression of systemic inflammation.…”

Docosahexaenoic Acid–Derived Fatty Acid Esters of Hydroxy Fatty Acids (FAHFAs) With Anti-inflammatory Properties

“…A wide range of lipid mediators, including resolvins D1 and D2, protectin D1, lipoxin A4, 17-hydroxydocosahexaenoic acid (HDHA), 18-HEPE, and 14-HDHA were identified in human subcutaneous WAT, whereas the levels of protectin D1 and 17-HDHA decreased in the subcutaneous WAT of patients with peripheral vascular disease (32). Protectin DX, also known to be produced in WAT, alleviated insulin resistance in db/db mice, but did not resolve WAT inflammation (33).…”

PGC-1α-mediated changes in phospholipid profiles of exercise-trained skeletal muscle

“…Docosahexaenoic acid [22:6 (n-3)] may have another function after being released from membrane glycerophospholipids by phospholipase A2, because D series resolvins and protectins derived from docosahexaenoic acid [22:6 (n-3)] have anti-infl ammatory and immunoregulatory properties (50)(51)(52)(53)(54). Recently, protectin DX, also derived from docosahexaenoic acid [22:6 (n-3)], was reported to stimulate the release of the prototypic myokine, interleukin-6, from skeletal muscle and thereby initiated a myokine-liver signaling axis, which blunted hepatic glucose production ( 55 ). Protectin DX also activates AMP-activated protein kinase ( 55 ), which stimulates glucose and lipid metabolism in skeletal muscle.…”

“…Recently, protectin DX, also derived from docosahexaenoic acid [22:6 (n-3)], was reported to stimulate the release of the prototypic myokine, interleukin-6, from skeletal muscle and thereby initiated a myokine-liver signaling axis, which blunted hepatic glucose production ( 55 ). Protectin DX also activates AMP-activated protein kinase ( 55 ), which stimulates glucose and lipid metabolism in skeletal muscle. From these facts, some of the health benefi ts of exercise training may be explained by PGC-1 ␣ -mediated alteration of skeletal muscle phospholipid profi les.…”