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Rare Antagonistic Leptin Variants and Severe, Early-Onset Obesity
Jan-Bernd Funcke1, Barbara Moepps1, Julian Roos1
1From the Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine (J.-B.F., J.R., J.S., K.K., A.N., S.B., P.F.-P., M.W.), the Institute of Experimental and Clinical Pharmacology, Toxicology, and Pharmacology of Natural Products (B.M., P.G.), and the Department of Pediatrics and Adolescent Medicine (K.-M.D.), Ulm University Medical Center, Ulm, Germany; the Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas (J.-B.F.); the Unit for Structural Biology, Vlaams Instituut voor Biotechnologie (VIB) Center for Inflammation Research, Department of Biochemistry and Microbiology, Ghent University, Ghent, Belgium (K.V., A.T., A.D., S.N.S.); the Division of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University Graz, Graz, Austria (E.F.-R., E.S.); the Division of Endocrinology, Department of Pediatrics, Sidra Medicine, Doha, Qatar (B.H., K.H.); and Wellcome Trust-Medical Research Council Institute of Metabolic Science and NIHR Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, United Kingdom (I.S.F.).
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.).
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