ESPEYB20 9. Obesity and Weight Regulation Genetic Obesity and Genetic Risk Score (3 abstracts)
9.7. Rare antagonistic leptin variants and severe, early-onset obesity
Funcke JB , Moepps B , Roos J , von Schnurbein J , Verstraete K , Fröhlich-Reiterer E , Kohlsdorf K , Nunziata A , Brandt S , Tsirigotaki A , Dansercoer A , Suppan E , Haris B , Debatin KM , Savvides SN , Farooqi IS , Hussain K , Gierschik P , Fischer-Posovszky P & Wabitsch M
N Engl J Med 2023, 388(24):2253–2261. Doi: 10.1056/NEJMoa2204041. https://pubmed.ncbi.nlm.nih.gov/37314706/.
Brief summary: The authors provide the first description of antagonistic hormone mutations as the cause of congenital disease in humans. The paper describes detailed characterizations of two novel, antagonistic leptin mutations underlying a formerly unrecognized form of congenital leptin dysfunction and delineate the challenges these mutations pose to the diagnosis and therapy of the disease.
After the initial description of biologically inactive leptin variants in 2015 (1), it has been expected that sooner or later patients would be identified who had an antagonizing leptin variant. Based on the knowledge of the molecular ligand-receptor interaction of leptin and its receptor, the existence of antagonizing variants of leptin in humans was likely.
Here, the authors show that specific rare human gene variants in the leptin gene result in leptin molecules with impaired interaction with site III of the leptin receptor responsible for receptor activation, but have high affinity to interaction site II which is responsible for receptor binding. These leptin variants block the leptin receptor when metreleptin is administered and behave as antagonizing ligands at the receptor level, leading to resistance to metreleptin.
Elaborate in vitro experiments paved the way for a successful therapy. Based on dose-response experiments applying heterologous cell systems and the expression of the gene variants in vitro, the authors were able to calculate the metreleptin dose needed to overcome leptin receptor antagonism in vivo. This was the basis for successful clinical treatment with relatively high dose metreleptin without side effects.
The collaborative work of scientists in experimental and clinical medicine in this center for genetic obesity was the basis for a personalized, mechanism-based treatment of the patients.
Reference: 1. Wabitsch M, Funcke JB, Lennerz B, Kuhnle-Krahl U, Lahr G, Debatin KM, Vatter P, Gierschik P, Moepps B, Fischer-Posovszky P: Biologically inactive leptin and early-onset extreme obesity. N Engl J Med 2015, 372(1):48–54.
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ESPE Yearbook of Paediatric Endocrinology
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