Mechanisms Underlying Weight Regain After GLP-1RA Treatment: A Neurobiological Perspective

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.