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.

Leptin replacement therapy for the treatment of non-HAART associated lipodystrophy syndromes: a meta-analysis into the effects of leptin on metabolic and hepatic endpoints

“…Of those, 26 were excluded mainly due to not being population-based data (case reports) or review articles and two of these studies were excluded as they represented data sets based on duplicated results from previous studies (20,21). Overall, 12 studies were included for data analysis (14,16,(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). Figure 1 illustrates the flow diagram outlining literature search strategy and study selection.…”

“…Quality percentage scores based on a modified QUADAS 2 tool ranged from 25% (30) to 75% (16,23), and the overall mean score was 56.3 ± 14.6% (Table 1).…”

Metreleptin for metabolic disorders associated with generalized or partial lipodystrophy

“…A common finding after prolonged leptin therapy is the development of leptin antibodies. Both neutralizing [47] and non-neutralizing [25] antibodies have been reported, and may underlie some cases of apparent resistance or poor response to leptin therapy [47]. It is also possible that development of neutralizing antibodies might not only diminish the therapeutic effect of exogenous leptin, but may also worsen underlying metabolic abnormalities by blocking the effects of endogenous leptin in those patients without severe hypoleptinemia.…”

Síndrome de Berardinelli-Seip: descrição genética e metabólica de cinco pacientes

“…Tendo em vista a importância da leptina na fisiopatologia dos principais distúrbios metabólicos encontrados na BSCL, alguns grupos analisaram a reposição de leptina humana recombinante como forma de interferir nesta evolução (11,(36)(37)(38)(39). Oral e cols.…”