Beyond the GH–IGF-1 Axis: A Network Perspective Integrating Clinical Observations and Mechanistic Insights

Background: Obesity encompasses a heterogeneous group of conditions that include not only simple obesity, but also genetic and endocrine disorders. The growth hormone (GH)-insulin-like growth factor 1(IGF-1) axis plays a central role in body composition, insulin sensitivity, and metabolic regulation. We encountered three patients in whom the clinical courses highlighted distinct interactions between obesity and the GH-IGF-1 axis. Methods: We reviewed three representative cases. Case 1 involved acromegaly improved by the peroxisome proliferator-activated receptor-α (PPAR-α) agonist pemafibrate. Case 2 involved Prader-Willi syndrome (PWS) with severe obesity treated using dulaglutide. Case 3 involved severe obesity managed with behavioral therapy. Clinical characteristics and therapeutic responses were analyzed. Results: In Case 1, pemafibrate administration resulted in a marked and sustained reduction in IGF-1 levels despite ongoing lanreotide therapy, suggesting a potential hepatic or pituitary interaction between PPAR-α signaling and GH-IGF-1 regulation. In Case 2, dulaglutide induced weight loss and reduced insulin requirements in a patient with PWS, a condition characterized by high levels of ghrelin. The therapeutic effect may involve modulation of ghrelin, an upstream regulator of GH secretion. In Case 3, behavioral therapy stabilized metabolic deterioration in a patient with a body mass index of 50.7 kg/m2, even though GH and IGF-1 levels remained low after weight reduction, suggesting mechanisms independent of the GH-IGF-1 axis. Conclusion: These findings support a conceptual shift from a linear GH-IGF-1 axis to an integrated GH-IGF-1 network that connects peripheral signals, hypothalamic regulation, and higher brain functions, offering a novel framework for personalized obesity management.