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

• Published in: European journal of endocrinology Vol. 162; no. 6; pp. 1083 - 1091
• Main Authors: Beltrand, Jacques, Lahlou, Najiba, Le Charpentier, Tifenn, Sebag, Guy, Leka, Sofia, Polak, Michel, Tubiana-Rufi, Nadia, Lacombe, Didier, de Kerdanet, Marc, Huet, Frederic, Robert, Jean-Jacques, Chevenne, Didier, Gressens, Pierre, Lévy-Marchal, Claire
• Format: Journal Article
• Language: English
• Published: Bristol BioScientifica 01.06.2010; European Society of Endocrinology
• Subjects: Adolescent; Antibodies, Neutralizing - immunology; Antibodies, Neutralizing - metabolism; Associated diseases and complications; Biological and medical sciences; Blood Glucose - metabolism; Body Composition; Child; Child, Preschool; Clinical Study; Diabetes. Impaired glucose tolerance; Drug Administration Schedule; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Female; Fundamental and applied biological sciences. Psychology; Humans; Leptin - administration & dosage; Leptin - metabolism; Lipid Metabolism; Lipids - blood; Lipodystrophy, Congenital Generalized - immunology; Lipodystrophy, Congenital Generalized - metabolism; Lipodystrophy, Congenital Generalized - therapy; Liver - metabolism; Male; Medical sciences; Patient Selection; Prospective Studies; Statistics, Nonparametric; Treatment Outcome; Vertebrates: endocrinology; Endocrinopathy; Resistance; Skin disease; Replacement therapy; Berardinelli lipodystrophy; Congenital; Leptin; Adipose tissue disorders; Adipokine; Congenital disease; Endocrinology; Genetic disease
• ISSN: 0804-4643; 1479-683X; 1479-683X
• DOI: 10.1530/EJE-09-1027

ContextRecently, 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 methodsA 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.ResultsA 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.ConclusionUnder leptin therapy, patients with BSCL may develop a resistance to leptin, which could be partly of immunological origin, blunting the previously reported beneficial effects.