Activation of PPARα can attenuate lipid accumulation and insulin resistance in rodents (1). Our recent studies have shown a close association of the activation of unfolded protein response (UPR) signalling pathways with hepatic insulin resistance in high fructose fed mice (2). The present study investigated whether the insulin sensitising effect of PPARα activation may be related to a relief of ER stress. The study was performed in insulin resistant mice induced by a high fat diet (HFD) treated with fenofibrate (FB, 100mg/kg/day), a well-recognized PPARα agonist. FB treatment corrected HFD-induced glucose intolerance and impairment of hepatic insulin signalling transduction (restoration of insulin’s ability to phosphorylate Akt & GSK3β) along with the activation of PPARα (evidenced by increased ACOX1 expression). Intriguingly, this was associated with substantial activation of two arms of UPR signalling, namely the IRE/XBP1 and PERK/eIF2α. Despite an enhanced rate of fatty acid oxidation, FB supplementation did not lower hepatic triglyceride, diacylglycerols, ceramide, nor did it alter the UPR downstream serine/threonine kinases (JNK and IKK) proposed to link activated UPR to insulin resistance. These results appear to be paradoxical to the reported role of increased UPR signalling as a mechanism contributing to hepatic steatosis and insulin resistance. Our findings clearly dissociate activated UPR signalling from hepatic steatosis and insulin resistance and provide a paradigm to further investigate whether the upstream of the UPR signalling may instead be a mediator for the observed metabolic effects induced by PPARα activation.

1. Ye JM, et al. (2001) Peroxisome proliferator-activated receptor (PPAR)-alpha activation lowers muscle lipids and improves insulin sensitivity in high fat-fed rats: comparison with PPAR-gamma activation. Diabetes 50(2):411-417.
2. Ren LP, et al. (2012) Differing endoplasmic reticulum stress response to excess lipogenesis versus lipid oversupply in relation to hepatic steatosis and insulin resistance. PLoS One 7(2):e30816.