Measurement of immunofunctional leptin to detect and monitor patients with functional leptin deficiency.

Martin Wabitsch,Pamela Fischer-Posovszky,Michael Schaab,Peter Gierschik,Michael Ranke,Julia Von Schnurbein,Bertram Flehmig,Katja Kohlsdorf,Barbara Moepps,Jan-Bernd Funcke,Lutz Pridzun,Jürgen Kratzsch,Anja Moss,Stephanie Brandt

doi:10.1530/eje-16-0821

Martin Wabitsch, Pamela Fischer-Posovszky + Show 12 more

Open Access

https://doi.org/10.1530/eje-16-0821

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Abstract

Context and aimsFunctional leptin deficiency is characterized by high levels of circulating immunoreactive leptin (irLep), but a reduced bioactivity of the hormone due to defective receptor binding. As a result of the fact that affected patients can be successfully treated with metreleptin, it was aimed to develop and validate a diagnostic tool to detect functional leptin deficiency.MethodsAn immunoassay capable of recognizing the functionally relevant receptor-binding complex with leptin was developed (bioLep). The analytical quality of bioLep was validated and compared to a conventional assay for immune-reactive leptin (irLep). Its clinical relevance was evaluated in a cohort of lean and obese children and adults as well as in children diagnosed with functional leptin deficiency and their parents.ResultsIn the clinical cohort, a bioLep/irLep ratio of 1.07 (range: 0.80–1.41) was observed. Serum of patients with non-functional leptin due to homozygous amino acid exchanges (D100Y or N103K) revealed high irLep but non-detectable bioLep levels. Upon treatment of these patients with metreleptin, irLep levels decreased, whereas levels of bioLep increased continuously. In patient relatives with heterozygous amino acid exchanges, a bioLep/irLep ratio of 0.52 (range: 0.48–0.55) being distinct from normal was observed.ConclusionsThe new bioLep assay is able to diagnose impaired leptin bioactivity in severely obese patients with a homozygous gene defect and in heterozygous carriers of such mutations. The assay serves as a diagnostic tool to monitor leptin bioactivity during treatment of these patients.

Highlights

The leptin/leptin receptor system is crucial for the regulation of body weight [1, 2]
The diagnosis in first patients described with bio-inactive leptin as the cause of extreme obesity had to be established by complex molecular genetic investigations [10]
We validated the binding complex with leptin was developed (bioLep) assay clinically in a large cohort with a wide age and BMI range and demonstrated that it is capable of measuring leptin concentrations in serum as reliably and accurately as conventional immunoassays

Summary

Introduction

The leptin/leptin receptor system is crucial for the regulation of body weight [1, 2]. Leptin is mainly produced in white adipocytes and secreted into the circulation [1, 3, 4]. Leptin reflects the body’s energy stores in adipose tissue and regulates body energy homeostasis as well as adipose tissue mass in a complex circuit involving central nervous pathways. Beginning in infancy, affected children show an insatiable appetite and hyperphagia resulting in an extreme debilitating, often life-threatening obesity and hypogonadotropic hypogonadism at pubertal age [5, 6, 9]

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