The Journal of Clinical Investigation · 2 authors, 1 centre
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This narrative review synthesizes current evidence on how incretin-mimetic drugs achieve unprecedented weight loss through dual mechanisms: sustained appetite suppression via gut-brain signaling and prevention of adaptive responses to weight loss via AgRP neuron inhibition.
This narrative review by Gou and Schwartz examines mechanisms underlying the unprecedented weight loss efficacy of incretin-mimetic drugs, including GLP-1 receptor agonists, dual GIP/GLP-1 agonists (tirzepatide), and a triple agonist (retatrutide). The authors synthesize evidence that these drugs achieve weight loss through two distinct mechanisms: potent activation of gut-brain signaling to continuously suppress appetite, and inhibition of AgRP neurons that mediate adaptive responses to weight loss. A phase II trial of retatrutide demonstrated 24.2% weight reduction after 48 weeks. Semaglutide treatment for 20 weeks reduced daily calorie intake by approximately one-third despite 10% body weight loss, counteracting normal adaptive feeding responses. The authors highlight concerns including rapid weight regain after drug discontinuation due to reactivation of energy homeostasis defenses, and the unknown long-term consequences of continuous multi-receptor hormone activation. They suggest future drug development could target specific neuronal subsets rather than widely distributed hormone receptors.
