MC4R agonist therapy in acquired hypothalamic obesity after craniopharyngioma surgery: rapid BMI reduction and weight rebound after withdrawal

Background: A 15-year-old girl presented to the Emergency Department with recent-onset frontal headache, visual impairment, right medial hemianopsia, and primary amenorrhea. Personal and family history were unremarkable, and she reported a healthy lifestyle with age-appropriate physical activity. Neuroimaging confirmed craniopharyngioma, and transsphenoidal resection was performed. The postoperative course was complicated by panhypopituitarism requiring desmopressin, glucocorticoid replacement, growth hormone, L-thyroxine, and oestrogen-progestin therapy. From the second postoperative month, a rapid and progressive increase in body weight was observed (BMI 21.1 kg/m² at diagnosis; 33.4 kg/m² at 6 months; 38.1 kg/m² at 18 months). Acquired hypothalamic obesity represents a severe and difficult-to-treat complication after craniopharyngioma surgery, reflecting disruption of central energy-balance pathways. Methods: Weight gain was considered multifactorial, predominantly related to hypothalamic injury affecting anorexigenic signalling and energy expenditure. Behavioural adaptations, psychological burden, and secondary endocrine factors were also evaluated. Hormonal reassessment confirmed adequate replacement therapy, while nutritional counselling and a structured physical-activity program were reinforced. Magnetic resonance imaging reconstructions further characterized hypothalamic involvement and supported the diagnosis of acquired hypothalamic obesity. Following Italian authorization (Law 648/96), treatment with setmelanotide, a selective melanocortin-4 receptor (MC4R) agonist targeting the leptin-melanocortin pathway, was initiated at 1 mg/day for three weeks and escalated to 2 mg/day thereafter. Results: Setmelanotide therapy was associated with a rapid and sustained BMI reduction, decreasing from 38.1 kg/m² (November 2024, pre-treatment) to 34.2 kg/m² (December 2024), 30.8 kg/m² (January 2025), 30 kg/m² (March 2025), 26.5 kg/m² (April 2025), 25 kg/m² (June 2025), and 22.9 kg/m² (July 2025). Treatment was discontinued because of the marked and rapid weight loss achieved. After discontinuation, BMI increased to 27 kg/m² by September 2025; reintroduction at a lower dose (0.5 mg/day) resulted in weight stabilization (BMI 27 kg/m² in October 2025). No unexpected adverse events were reported, and hormone replacement therapy required no clinically relevant adjustments. Conclusions: This case highlights the dynamic trajectory of acquired hypothalamic obesity after craniopharyngioma surgery and supports melanocortin-pathway modulation as a targeted therapeutic strategy. The observed weight rebound after treatment withdrawal suggests that sustained MC4R agonist therapy may be required to maintain metabolic control in patients with hypothalamic injury.