From Gut to Brain: The Neurohormonal Basis of Appetite Suppression and Gastric Emptying Delay by Semaglutide in Non-Diabetic Obesity

Abstract

Background: Obesity is a chronic disease that is caused by dysregulation of the neurohormonal systems that regulate energy balance. With a weight loss of around 15% in randomized phase 3 trials, Semaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1 RA) with greater weight-loss results than any other approved pharmacotherapy. The efficacy is due to the concurrent activation of hypothalamic appetite pathways, peripheral satiety hormones and enteric motility pathways. Methods: A narrative review of peer-reviewed literature was performed from 2015 to 2026. The following databases were searched: PubMed (MEDLINE), Scopus, and Google Scholar. The evidence was categorized in five mechanistic areas: the pharmacology of GLP-1 receptor, hypothalamic control of appetite and energy expenditure, peripheral satiety hormones, gut-brain axis signaling, and gastric motility. The strength of the evidence is indicated throughout, based on randomized trials, preclinical models, or observational studies. Results: Semaglutide acts directly in the arcuate nucleus on GLP-1 receptor (GLP-1R) to inhibit orexigenic (for eating) NPY/AgRP neurons and enhance anorexigenic (appetite suppressant) POMC/CART signaling. This central effect is further enhanced by peripheral ghrelin suppression, increased postprandial insulin secretion, and increased vagal afferent satiety signals. Gastric emptying delay (via enteric GLP-1 receptor activation, vagal efferent cholinergic drive, and suppression of motilin) extends postprandial gastric distention, which strengthens the central satiety signal. This gastric effect is most significant when dosed initially for dose titration and then may decrease following chronic dosing. Conclusion: Semaglutide acts directly in the arcuate nucleus on GLP-1 receptor (GLP-1R) to inhibit orexigenic (for eating) NPY/AgRP neurons and enhance anorexigenic (appetite suppressant) POMC/CART signaling. This central effect is further enhanced by peripheral ghrelin suppression, increased postprandial insulin secretion, and increased vagal afferent satiety signals. Gastric emptying delay (via enteric GLP-1 receptor activation, vagal efferent cholinergic drive, and suppression of motilin) extends postprandial gastric distention, which strengthens the central satiety signal. This gastric effect is most significant when dosed initially for dose titration and then may decrease following chronic dosing.