Central actions of glucagon-like peptide-1 on food intake and reward: Novel neurological targets and sex divergent effects

Abstract

Obesity is one of the biggest health risks of our society; however, treatment options are sparse and often result in suboptimal weight-loss. The glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonist liraglutide was recently approved for treatment of obesity in the US. GLP-1, and synthetic analogues, reduce body weight by suppressing food intake and food reward through actions on GLP-1Rs in the CNS. Regulation of homeostatic and hedonic feeding, by GLP-1, was previously attributed to actions specifically within the hypothalamus or limbic system, respectively. Our studies chal-lenge this view and demonstrate novel central areas mediating the effects of GLP-1R stimulation on food intake and reward. Using standard food intake and body weight measurements, and reward behavior tests, we demonstrate that GLP-1R stimulation, using GLP-1R agonist exendin-4 (Ex4), reduces food intake and food reward behavior through actions in the nucleus of the solitary tract (NTS) and lateral hypothalamus (LH). In addition, NTS GLP-1 neurons were found in close proximity to noradrenergic neurons, and intra-NTS Ex4 injection increased dopamine-related genes in the ventral tegmental area, suggesting a link between the NTS and the reward system. Furthermore, the parabrachial nucleus (PBN) was identified as a novel area mediating the anorexic effects of GLP-1R stimulation. This thesis also demonstrates potential sex differences in the effects of GLP-1, and its agonists, as central GLP-1R stimulation suppresses food-motivated behavior to a larger degree in females compared to males. In addition, central estrogen, and estrogen receptor-α (ERα), blockade attenuate the effects of Ex4 on food reward, but not food intake. However, specifically within the LH, GLP-1R stimulation is sufficient to reduce food-motivated behavior in both sexes, while it is only necessary in males. In conclusion, effects of GLP-1R stimulation on food intake and food reward are not bound to actions on GLP-1Rs exclusively within homeostatic or hedonic feeding cen-ters. Furthermore, GLP-1-mediated food reward, but not food intake, suppression is dependent on estrogen signaling. However, GLP-1 may also act differently within specific brain nuclei, as LH GLP-1R stimulation is sufficient to reduce food-reward in both sexes, while it is only necessary for its actions in males.