Leptin is a type I cytokine and belongs to the long-chain helical cytokine subfamily just as GH, IL-6 and G-CSF. Leptin is produced mainly in white adipose tissue and thereby reflects body energy stores. Leptin serum concentrations are high in obese and low in underweight individuals or in those with low body fat e.g. in athletes and in patients with lipodystrophy. The leptin/leptin receptor system is crucial for the regulation of body weight. Rare homozygous mutations in the leptin gene can lead to defects in synthesis and/or secretion of leptin resulting in congenital leptin deficiency with low or undetectable serum levels of leptin. Affected children show an insatiable appetite and food seeking behaviour, excessive weight gain and a multitude of metabolic and hormonal disturbances including hypogonadotropic hypogonadism. Patients can be effectively treated by substitution with recombinant human leptin (metreleptin). Recently, we have described mutations in the leptin gene which result in secreted proteins which are however not able to activate the leptin receptor due to structural alterations in binding site II. Affected patients have high circulating leptin levels which appear to be appropriate for their fat mass. Their clinical presentation is similar to that of patients with classical leptin deficiency. As these patients can also be treated effectively with metreleptin we have developed an immunoassay which measures only the bioactive fraction of total serum leptin capable to bind to the receptor in order to facilitate early diagnosis. In conclusion, patients have shown us the occurrence of functional leptin deficiency. Interestingly, mutagenesis studies suggest that other mutations in the leptin gene might occur resulting in diverse alterations in protein sequence, secretion, structure and receptor interaction. Theoretically, affected patients would need specific diagnostic workup and treatment regimes depending on the underlying molecular defect.
27 - 29 Sep 2018
European Society for Paediatric Endocrinology