ESPE Abstracts

Introduction: The soluble leptin receptor (sLR) is the main binding protein of leptin in the serum. It reflects the amount of membrane-bound leptin receptors (LEPR) as the sLR is produced by proteolytic cleavage of the extracellular domain of membrane-bound LEPR. Low sLR but high leptin levels were measured in patients with severe obesity. In patients with monogenic obesity caused by biallelic LEPR variants, sLR levels were found to be either undetectable or extremely high, leading to high circulating leptin levels. The aim of this analysis was to investigate whether a disease-causing LEPR variant results in low or high sLR levels in patients with biallelic LEPR variants.

Methods: 13 patients with disease-causing biallelic LEPR variants presented to our outpatient clinic were included. SLR levels were measured using the Enzyme-linked Immunosorbent Assay (kit R07, Mediagnost, Reutlingen, Germany), which is a Sandwich-Assay using two specific high-affinity antibodies against the sLR in the serum. Anthropometric and laboratory parameters such as lipids, liver enzymes, parameters of glucose metabolism, thyroid hormones, sex hormones, growth hormones, bioactive and total leptin levels were assessed at the first visit to our outpatient clinic.

Results: Patients with biallelic LEPR variants due to frameshift or nonsense variants (n= 7) had significant lower sLR levels than patients with biallelic LEPR variants due to missense variants (n= 6) (0.57 ± 0.33 ng/mL versus 7.05 ± 6.87 ng/mL, p <0.05). Patients with nonsense/frameshift variants had a significant higher BMI SDS (4.57 ± 0.59 versus 3.38 ± 0.75, p <0.05), and a trend toward lower leptin SDS (-7.02 ± 6.14 versus -0.83 ± 3.91, P= 0.057) than patients with missense variants. There were no significant differences in the laboratory parameters between patients with frameshift/nonsense and missense variants. After adjusting for sex, age and BMI, patients with frameshift/nonsense variants presented significantly higher adjusted means for cholesterol (5.79 ± 0.63 mmol/L versus 2.71 ± 0.32 mmol/L, p <0.05), LDL cholesterol (4.21 ± 0.67 mmol/L versus 2.11 ± 0.34 mmol/L, P= 0.05) and TSH (4.72 ± 0.59 mIU/L versus 2.47 ± 0.3 mIU/L, p <0.05) than patients with missense variants.

Conclusion: In contrast to patients with biallelic LEPR variants due to missense variants, patients with frameshift or nonsense variants have extremely low sLR levels and are thus discriminable. Patients with frameshift or nonsense variants are associated with a more severe obesity phenotype than patients with missense variants. Future studies are required to verify these results.