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Resistance to leptin-replacement therapy in Berardinelli-Seip congenital lipodystrophy: an immunological origin

Research output: Contribution to journalArticle

Jacques Beltrand, Najiba Lahlou, Tifenn Le Charpentier, Guy Sebag, Sofia Leka, Michel Polak, Nadia Tubiana-Rufi, Didier Lacombe, Marc de Kerdanet, Frederic Huet, Jean-Jacques Robert, Didier Chevenne, Pierre Gressens, Claire Lévy-Marchal

Original languageEnglish
Article numberN/A
Pages (from-to)1083-1091
Number of pages9
JournalEuropean journal of endocrinology / European Federation of Endocrine Societies
Volume162
Issue number6
DOIs
Publication statusPublished - Jun 2010

King's Authors

Abstract

Context: Recently, in a 4-month proof-of-concept trial, beneficial metabolic effects were reported in non-diabetic children with Berardinelli–Seip congenital lipodystrophy (BSCL); this information prompted us to hypothesize that long-term leptin-replacement therapy might improve or reverse the early complications of the disease in these patients.

Patients and methods: A 28-month trial was implemented in eight patients. Efficacy assessment was based on a decrease in serum triglyceride concentrations, and/or a decrease in liver volume and/or an increase in insulin sensitivity of at least 30% respectively. The response was defined as follows: total (3/3 positive criteria), partial (1 or 2/3), or negative (0/3). Anti-leptin antibodies were measured with a radiobinding assay, and a neutralizing effect was assessed in primary cultures of embryonic neurons incubated with an apoptotic agent (N-methyl-D-aspartate) and the patient serum, with or without leptin.

Results: A negative or partial response to treatment was observed in five of eight patients even when leptin dosages were increased. A displaceable leptin binding was detectable in all patients after 2 months of treatment. At 28 months, binding was higher in the patients with a negative response than in the total responders, and it paralleled both the increase in leptin dosage and serum leptin concentrations. Co-incubation of embryonic neurons with serum from two patients with a negative response inhibited the neuroprotective effect of leptin.

Conclusion: Under leptin therapy, patients with BSCL may develop a resistance to leptin, which could be partly of immunological origin, blunting the previously reported beneficial effects.

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