Protective effect of liraglutide against ER stress in the liver of high-fat diet-induced insulin-resistant rats

The purpose of this study was to investigate whether the glucagon-like peptide-1 (GLP-1) analog liraglutide can alleviate endoplasmic reticulum (ER) stress and insulin resistance (IR) in the liver of high-fat diet-induced insulin-resistant rats. Eighty-five male Sprague–Dawley rats were fed with normal chow or a high-fat diet for 12 weeks. The IR was evaluated using the hyperinsulinemic-euglycemic clamp technique. The rats in the HF group were further divided into four groups and were treated with or without liraglutide by subcutaneous injection. Body weight (BW), fasting blood glucose (FBG), fasting insulin (FINS), and insulin sensitivity were measured. The expression of ER stress marker GRP78 and its signaling mediators, such as IRE1α, PERK, and ATF6, in the liver were examined. The ultrastructure of the ER in the liver was examined by transmission electron microscopy. The expression levels of chemerin in the liver and the serum were also measured. After 4 weeks of liraglutide treatment, the BW, FBG, and FINS levels were significantly reduced, and the insulin sensitivity was increased compared with the HF only rats. Liraglutide reduced the expression of GRP78 and chemerin in liver tissue at both the mRNA and protein levels. Interestingly, the chemerin mRNA was closely correlated with the level of GRP78 mRNA, while the level of chemerin in serum was also associated with the FINS level. As a representative GLP-1 analog, liraglutide can suppress ER stress and reduce chemerin expression in the liver of rats exposed to a high-fat diet.