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

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.

• Authors: 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
• Journal: European journal of endocrinology (Eur J Endocrinol) Vol. 162 Issue 6 Pg. 1083-91 (Jun 2010) ISSN: 1479-683X [Electronic] England
• PMID: 20236991 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Neutralizing
• Blood Glucose
• Leptin
• Lipids

Topics

• Adolescent
• Antibodies, Neutralizing (immunology, metabolism)
• Blood Glucose (metabolism)
• Body Composition
• Child
• Child, Preschool
• Drug Administration Schedule
• Female
• Humans
• Leptin (administration & dosage, metabolism)
• Lipid Metabolism
• Lipids (blood)
• Lipodystrophy, Congenital Generalized (immunology, metabolism, therapy)
• Liver (metabolism)
• Male
• Patient Selection
• Prospective Studies
• Statistics, Nonparametric
• Treatment Outcome