Rare Antagonistic Leptin Variants and Severe, Early-Onset Obesity

This study describes two novel homozygous leptin variants (P64S and G59S) identified in unrelated children with severe early onset obesity and hyperphagia. Unlike typical leptin deficiencies, these variants produced antagonistic proteins that bound to the leptin receptor (LEPRb) but triggered minimal signaling, competitively inhibiting nonvariant leptin. Treatment with high dose recombinant leptin (metreleptin) overcame this antagonism, leading to near normal weight in both patients. The study highlights the importance of functional characterization of leptin variants for accurate diagnosis and personalized treatment, demonstrating that hormone antagonism can underlie congenital leptin dysfunction.

This study describes two novel homozygous leptin variants (P64S and G59S) identified in unrelated children with severe early onset obesity and hyperphagia. Unlike typical leptin deficiencies, these variants produced antagonistic proteins that bound to the leptin receptor (LEPRb) but triggered minimal signaling, competitively inhibiting nonvariant leptin. Treatment with high dose recombinant leptin (metreleptin) overcame this antagonism, leading to near normal weight in both patients. The study highlights the importance of functional characterization of leptin variants for accurate diagnosis and personalized treatment, demonstrating that hormone antagonism can underlie congenital leptin dysfunction.