Fenofibrate improves high-fat diet-induced and palmitate-induced endoplasmic reticulum stress and inflammation in skeletal muscle

AimsFenofibrate (FF) is commonly used clinically as a lipid-lowering drug, but whether it participates in endoplasmic reticulum (ER) stress and decreases inflammation in skeletal muscle is still unknown. The aim of this study is to determine whether FF treatment reduces insulin resistance (IR) by alleviating ER stress and downstream inflammation in skeletal muscle tissues and cells.Main methodsFemale SD rats were randomly divided into groups receiving the standard chow diet (SCD), a high-fat diet (HFD), or HFD plus FF (HFD + FF). The rats in the latter two groups were subjected to a standard HFD for 20 weeks, then the HFD + FF rats were administered FF (30 mg/kg once daily via gavage) for another 8 weeks. Whole-body IR, expression of peroxisome proliferator-activated receptor α (PPARα), ER stress-related genes, and inflammatory genes in the soleus muscle were assessed. The differentiated C2C12 myotubes were treated with palmitic acid or pretreated with fenofibric acid or 4-phenylbutyric acid (4-PBA), etomoxir, and the expression of ER stress, beta-oxidation-related genes, inflammatory genes, Toll-like receptor 4 (TLR4), and insulin-signaling-related molecules were determined.Key findingsEight weeks of FF treatment attenuated HFD-induced IR by decreased tribbles 3 (TRB3) expression, ER stress and inflammation in skeletal muscle. FA pretreatment markedly inverted the PA-induced expression of TLR4 and downstream inflammatory genes, activated ER stress, improved β-oxidation and insulin signaling in differentiated myotube cells.SignificanceFF treatment significantly improved HFD-induced IR in skeletal muscle and PA-induced IR in myotube cells, which may be related to reduced ER stress-induced inflammation.