Mechanisms Underlying Weight Regain After GLP-1RA Treatment: A Neurobiological Perspective
Kerolayne de Melo Nogueira *
Pitágoras College of Health Sciences of Codó, State of Maranhão, Brazil and Postgraduate Program in Pharmacology, Federal University of Ceará, Fortaleza, Brazil.
Ian Jhemes Oliveira Sousa
Pitágoras College of Health Sciences of Codó, State of Maranhão, Brazil, Federal University of Piauí, Posgraduate Program of Pharmacology and Northeast Biotechnology Network, Focal Point on - Federal University of Piauí – UFPI, Teresina, Brazil and IDOMED - Institute of Medical Education - UNIFACID Unit, Teresina, State of Piauí, Brazil.
*Author to whom correspondence should be addressed.
Abstract
Weight rebound after discontinuation of GLP-1 receptor agonists (GLP-1RAs) is common and often misinterpreted as a sign of weak willpower. This review summarizes preclinical and clinical evidence on how GLP-1RAs affect food stimulus processing and other systems that determine relapse risk, including gastrointestinal physiology, inflammatory signaling, and stress hormones. During treatment, GLP-1RAs can reduce binge eating and food stimulus-driven eating by decreasing the motivational value of highly palatable foods, including by modulating mesolimbic circuitry and glutamatergic signaling. With prolonged use, some reward-related responses may diminish, and food stimuli may become more prominent upon discontinuation, leading to a recurrence of food cravings and overeating. Persistent low-grade inflammation and enhanced stress responses may further amplify stimulus-driven eating and weaken inhibitory control. These interacting mechanisms collectively constitute a clinically meaningful framework for treating rebound effects and support maintenance approaches that combine pharmacological, behavioral, and lifestyle strategies to improve the long-term sustainability of weight loss.
Keywords: GLP-1 receptor agonists, weight regain, dopamine signaling, compulsive eating, neuroinflammation, neuroendocrine adaptation, mesolimbic reward circuit