When Genetics Meets Appetite: Tirzepatide in a Teenager with MC4R Deficiency

Dr. Gagan Priya, Consultant Endocrinology, Fortis Mohali

Tirzepatide led to meaningful weight loss and metabolic improvement in MC4R deficiency, but did not sustainably control genetic hyperphagia.

Monogenic obesity, most commonly driven by defects in the leptin–melanocortin pathway, remains one of the most challenging forms of pediatric obesity. Among these, melanocortin-4 receptor (MC4R) deficiency is the most frequent and is marked by early-onset obesity, intense hyperphagia, and rapid weight gain beginning in early childhood. By adolescence, many patients already present with type 2 diabetes risk, hypertension, and significant psychosocial burden.

A recent anonymous clinical case from a specialist obesity centre highlights the evolving therapeutic landscape. A 17-year-old girl with genetically confirmed MC4R deficiency (pathogenic MC4R variant) presented with grade 2 obesity and severe, persistent hyperphagia. Despite structured lifestyle interventions and high personal motivation, appetite control and BMI reduction remained limited.

Off-label tirzepatide, a dual GLP-1 and GIP receptor agonist, was initiated with gradual dose escalation. Early response included marked reduction in hunger scores (VAS 8/10 to 1–2/10) and clinically meaningful weight loss. Over nine months, body weight decreased by approximately 20.9% with low-dose metformin, accompanied by improved satiety and improved metabolic markers, including reduced triglycerides and HbA1c.

Importantly, appetite suppression was inconsistent over time, with periodic rebound hyperphagia despite continued weight loss. The drug was otherwise well tolerated, with only mild transient gastrointestinal symptoms.

This case suggests that while tirzepatide may significantly improve metabolic outcomes in MC4R deficiency, hyperphagia remains a complex, partially resistant symptom, underscoring the need for longer-term and targeted neuroendocrine strategies in genetic obesity.

(Reference: van der Walle EE, Boon MR, van Rossum EF, van den Akker EL. Tirzepatide and metformin effects on hunger and BMI in an adolescent with hyperphagia and severe obesity due to MC4R Deficiency: a case report. Obesity Facts. 2026 Apr 2.)