Abstract
Leukotriene B4 (LTB4) production via the 5-lipoxygenase (5-LO) pathway contributes to the development of insulin resistance in adipose and hepatic tissues, but the role of LTB4 in skeletal muscle is relatively unknown. Here, the authors investigated the role of LTB4 in C2C12 myotubes in palmitic acid (PA)-induced ER stress, inflammation and insulin resistance. PA (750 μM) evoked lipotoxicity (ER stress, oxidative stress, inflammation and insulin resistance) in association with LTB4 production. 5-LO inhibition reduced all the lipotoxic effects induced by PA. On the other hand, PA did not induce cysteinyl leukotrienes (CysLTs), which themselves had no effect on ER stress and inflammation. The beneficial effects of 5-LO suppression from PA-induced lipotoxicity were related with AMPK activation. In ob/ob mice, once daily oral administration of zileuton (50, 100 mg/kg) for 5 weeks improved insulin resistance, increased AMPK phosphorylation, and reduced LTB4 and ER stress marker expression in skeletal muscle. These results show that 5-LO inhibition by either zileuton or 5-LO siRNA protects C2C12 myotubes from PA-induced lipotoxicity, at least partly via AMPK activation, and suggest that the in vivo insulin-sensitizing effects of zileuton are in part attributable to its direct action on skeletal muscle via LTB4 downregulation followed by AMPK activation.
Highlights
The incidences of metabolic diseases, including type 2 diabetes mellitus (T2DM), continue to dramatically increase worldwide, possibly due to the obesity epidemic
We investigated the effects of 5-LO inhibition by either zileuton or 5-LO siRNA on palmitic acid (PA)-induced Endoplasmic reticulum (ER) stress and insulin resistance in C2C12 myotubes to assess the role of Leukotriene B4 (LTB4) in skeletal muscle
All cysLTs (i.e. LTC4, LTD4 and LTE4) had little effect on the expression of ER stress, proinflammatory markers, insulin signaling and glucose uptake (Supplementary Fig. 1). These results suggest that LTB4 produced by PA may act, at least partly, to induce ER stress, oxidative stress, inflammation, and insulin resistance possibly in an autocrine fashion
Summary
Leukotrienes are potent proinflammatory mediators, and the LTB4-BLT1 axis plays an important role in obesity-driven inflammation and insulin resistance[16]. AMPK activation has been shown to suppress ROS production and inflammation via NF-kB inhibition in T2DM patients[32] Consistent with such reports, our findings indicate zileuton significantly induces AMPK phosphorylation and subsequently ameliorates PA-induced ER stress and insulin resistance. In accord with our results, FLAP inhibition by Bay-X-1005 and LTB4 receptor antagonist (U75302) have been reported to induce AMPK phosphorylation in diet-induced obese mice, which suggests AMPK activation importantly underlies the protective effects exerted by 5-LO inhibition[22, 34]. In line with previous reports on zileuton in high fat diet-induced obese mice[15], daily zileuton (50 or 100 mg/kg) for 5 weeks reduced glucose intolerance, levels of ER stress markers, and enhanced AMPK phosphorylation in skeletal muscle. Our findings demonstrate that AMPK activation induced by skeletal 5-LO inhibition ameliorates murine insulin resistance, and highlight the possible therapeutic applications of 5-LO inhibition for the treatment of obesity-induced metabolic diseases like T2DM
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