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Diverse Obesity Trajectories in a Family Including Identical Twins with a Pathogenic MC4R Variant

Jane Jia Xin Lim1, Amanda J Hooper2,3, Joan Khoo4

  • 1Department of Endocrinology, Changi General Hospital, Singapore, Singapore, jane.lim94@gmail.com.

Obesity Facts
|June 25, 2025
PubMed

Insights

Monogenic obesity caused by melanocortin-4 receptor (MC4R) variants can manifest differently. Lifestyle and environmental factors significantly influence obesity presentation and treatment response.

Area of Science:

  • Genetics
  • Endocrinology
  • Obesity Research

Background:

  • Pathogenic heterozygous melanocortin-4 receptor (MC4R) variants are a leading genetic cause of monogenic obesity.
  • MC4R variants disrupt central appetite and satiety regulation in the brain.

Observation:

  • A family (pedigree) presented with a pathogenic MC4R variant (c.380C>T, p.Ser127Leu).
  • The proband, with obesity (BMI 35 kg/m2) and severe insulin resistance, showed improved weight and insulin sensitivity with semaglutide and naltrexone-bupropion.
  • Monozygotic twin daughters exhibited distinct obesity trajectories despite sharing the MC4R variant; one achieved normal BMI through lifestyle changes, while the other required medication (naltrexone-bupropion) to manage obesity.

Findings:

  • Obesity presentation and treatment response vary even with identical genetic predisposition (MC4R variant).
  • Intensive lifestyle interventions (diet, exercise) can effectively manage obesity in some individuals with monogenic obesity.
  • Pharmacological interventions (semaglutide, naltrexone-bupropion) show efficacy in managing obesity and related metabolic issues in MC4R variant carriers.

Implications:

  • Environmental and lifestyle factors play a crucial role in modulating the phenotypic expression of monogenic obesity.
  • Personalized treatment strategies considering genetic background and lifestyle are essential for effective obesity management.
  • Understanding the interplay between genetics and environment is key to developing targeted therapies for obesity.
Keywords:
GLP-1-RAMC4R mutationMonogenetic obesityNaltrexone-bupropionSemaglutide

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