Endoplasmic reticulum (ER) stress is suggested to cause hepatic insulin resistance by increasing de novo lipogenesis (DNL) and/or directly interfering with insulin signaling via activation of the JNK and IKK pathway. The present study interrogated these two proposed mechanisms in a mouse model of hepatic insulin resistance induced by a high fructose (HFru) diet with the treatment of fenofibrate (FB, 100 mg/kg/day), a PPARa agonist known to reduce lipid accumulation while maintaining elevated DNL in the liver. FB administration completely corrected HFru-induced glucose intolerance, hepatic steatosis and the impaired hepatic insulin signaling (pAkt and pGSK3ß). Intriguingly, both IRE1/XBP1 and PERK/eIF2a arms of the UPR signaling were activated. While retaining the elevated DNL (indicated by the upregulation of SREBP1c, ACC, FAS and SCD1 and 3H2O incorporation into lipids), FB treatment markedly increased FA oxidation (indicated by induction of ACOX1, pACC, ß-HAD activity and 14C-palmitate oxidation) and eliminated the accumulation of diacylglycerols (DAGs) which is known to impact on insulin signaling. Despite the marked activation of UPR signaling, neither JNK nor IKK appeared to be activated. These findings suggest that lipid accumulation (mainly DAGs), rather than the activation of JNK or IKK is pivotal for ER stress to cause hepatic insulin resistance. Therefore, by reducing the accumulation of deleterious lipids, activation of PPARa is able to ameliorate hepatic insulin resistance against increased ER stress
