GLP-1 and Dual GIP/GLP-1 Receptor Agonists in Pediatric Obesity: From Neuroendocrine Mechanisms to Clinical Application.

Pediatric obesity is a chronic, multifactorial neuroendocrine disease in which disrupted gut-brain signaling, hypothalamic appetite regulation, adipose tissue dysfunction, and altered inter-organ communication sustain positive energy balance. Incretin-based therapies translate this biology into mechanism-based treatment, yet their developmental implications remain incompletely defined. This narrative review integrates evidence on GLP-1 and GIP receptor signaling with pediatric trial data and clinical implementation, with particular attention to developmental modifiers of gut-brain signaling and treatment during growth and puberty. We describe how GLP-1 receptor agonists act across central and peripheral tissues to reduce appetite, delay gastric emptying, and enhance glucose-dependent insulin secretion and examine the rationale for dual GIP/GLP-1 receptor agonism. Randomized pediatric trials demonstrate clinically meaningful BMI reduction with liraglutide and semaglutide, with the largest mean effect reported for semaglutide in adolescents; however, long-term effects on growth, puberty, bone health, body composition, and weight maintenance remain uncertain. Tirzepatide has shown greater weight-loss efficacy than selective GLP-1 receptor agonism in adults, but no randomized trial has evaluated it in pediatric obesity without diabetes. Incretin-based therapies should be integrated with nutritional, behavioral, psychological, and family-based care. Their future value will depend on durable efficacy, developmental safety, equitable access, and identification of patients most likely to benefit.