Rare Antagonistic Leptin Variants and Severe, Early-Onset Obesity
Jan‐Bernd Funcke, Barbara Moepps, Julian Roos, Julia von Schnurbein, Kenneth Verstraete, Elke Fröhlich‐Reiterer, Katja Kohlsdorf, Adriana Nunziata, S. Brandt, Alexandra Tsirigotaki, Ann Dansercoer, Elisabeth Suppan, Basma Haris, Klaus‐Michael Debatin, Savvas N. Savvides, I. Sadaf Farooqi, Khalid Hussain, Peter Gierschik, Pamela Fischer‐Posovszky, Martin Wabitsch
Abstract
Hormone absence or inactivity is common in congenital disease, but hormone antagonism remains controversial. Here, we characterize two novel homozygous leptin variants that yielded antagonistic proteins in two unrelated children with intense hyperphagia, severe obesity, and high circulating levels of leptin. Both variants bind to the leptin receptor but trigger marginal, if any, signaling. In the presence of nonvariant leptin, the variants act as competitive antagonists. Thus, treatment with recombinant leptin was initiated at high doses, which were gradually lowered. Both patients eventually attained near-normal weight. Antidrug antibodies developed in the patients, although they had no apparent effect on efficacy. No severe adverse events were observed. (Funded by the German Research Foundation and others.).