Long‐acting glucagon‐like peptide‐1 receptor agonists have direct access to and effects on pro‐opiomelanocortin/cocaine‐ and amphetamine‐stimulated transcript neurons in the mouse hypothalamus

Liraglutide is a glucagon‐like peptide‐1 receptor (GLP‐1R) agonist marketed for the treatment of type 2 diabetes. Besides lowering blood glucose, liraglutide reduces bodyweight, and has recently also been approved for the obesity indication. Acutely, GLP‐1 markedly reduces gastric emptying, and this effect was previously believed to at least partly explain the effect on bodyweight loss. However, recent studies in both humans and animals have shown that GLP‐1R agonists, such as liraglutide, that lead to pharmacological concentrations for 24 h/day only have a minor effect on gastric emptying; such an effect is unlikely to have lasting effects on appetite reduction. Liraglutide has been shown to have direct effects in the arcuate nucleus of the rodent brain, activating pro‐opiomelanocortin neurons and increasing levels of the cocaine‐ and amphetamine‐stimulated transcript neuropeptide messenger ribonucleic acid, which correlate nicely to clinical studies where liraglutide was shown to increase feelings of satiety. However, despite the lack of a GLP‐1R on agouti‐related peptide/neuropeptide Y neurons, liraglutide also was able to prevent a hunger associated increase in agouti‐related peptide and neuropeptide Y neuropeptide messenger ribonucleic acid, again with a strong correlation to clinical studies that document reduced hunger feelings in patients while taking liraglutide. Studies using fluorescent labeled liraglutide, as well as other GLP‐1R agonists, and analysis using single‐plane illumination microscopy show that such medium‐sized peptide‐based compounds can directly access not only circumventricular organs of the brain, but also directly access discrete regions in the hypothalamus. The direct effects of long‐acting GLP‐1R agonists in the hypothalamus are likely to be an important new pathway in understanding GLP‐1R agonist mediated weight loss.