High‐fat feeding leads to decreased responsiveness to the GLP‐1 analogue, exendin‐4, in obesity‐prone (OP) rats

Abstract

We have recently shown that diet‐induced obese rats exhibit decreased responses to nutrient‐induced satiation, and this was associated with diminished protein expression of several gut peptides, including GLP‐1. Exogenous GLP‐1, and its analogue exendin‐4 (Ex‐4) decrease food intake, however, it is not known whether obese prone (OP) rats have an impaired response to GLP‐1, that could contribute to decreased nutrient induced satiation and hyperphagia. Therefore, we examined the effects of Ex‐4 on food intake in OP and obesity resistant (OR) rats maintained on either chow or high‐energy/high‐fat (HE/HF) diet. When exposed to chow, there was no difference in 1h food intake between OP and OR rats following Ex‐4 (0, 0.625, 1.25, 2.5, and 5 μg/kg, IP). However, when fed the HE/HF diet, OP suppressed intake significantly less than OR rats at all Ex‐4 doses tested. Also, compared to OR, OP rats expressed less GLP‐1 protein in the intestinal epithelium irrespective of the maintenance diet. There was with no difference in fasting GLP‐1 circulating plasma levels between OP and OR rats. Finally, HE/HF feeding resulted in downregulation of GLP‐1 mRNA expression in the vagal nodose ganglia of OP rats. We conclude that feeding a HE/HF diet leads to impaired feeding responses to GLP‐1 in OP rats, which is associated with diminished gene expression in the vagal afferents.