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


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.


CONCLUSIONS
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.
Unité INSERM U690, Hôpital Robert Debré, 48 Boulevard Sérurier, Paris, France. beltrand@me.com
Jacques
J
Beltrand
Najiba
N
Lahlou
Tifenn
T
Le Charpentier
Guy
G
Sebag
Sofia
S
Leka
Michel
M
Polak
Nadia
N
Tubiana-Rufi
Didier
D
Lacombe
Marc
M
de Kerdanet
Frederic
F
Huet
Jean-Jacques
JJ
Robert
Didier
D
Chevenne
Pierre
P
Gressens
Claire
C
Lévy-Marchal
D000293:Adolescent; D057134:Antibodies, Neutralizing / Q000276:immunology* / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D001823:Body Composition; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D020738:Leptin / Q000008:administration & dosage* / Q000378:metabolism; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood; D052497:Lipodystrophy, Congenital Generalized / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D008099:Liver / Q000378:metabolism; D008297:Male; D018579:Patient Selection; D011446:Prospective Studies; D018709:Statistics, Nonparametric; D016896:Treatment Outcome
D057134:Antibodies, Neutralizing; D001786:Blood Glucose; D020738:Leptin; D008055:Lipids