Purpose: Leptin plays a key role in the regulation of body weight and other endocrine systems. Recently, impairment of leptin gene transcription due to genetic variations in a long-noncoding RNA, also referred as lncOb, has been described in mice. In humans, a correspondent polymorphism (rs10487505) has been associated with relatively low plasmatic leptin levels compared to obesity severity and with early obesity onset.
Objectives: To characterize the clinical and metabolic phenotype of children and adolescents with obesity homozygous for lncOb rs10487505 leptin lowering allele.
Methods: children and adolescents attending the pediatric obesity clinic underwent an anthropometrical evaluation, standard 2-hour oral glucose tolerance test, and genotyping for lncOb rs10487505. Fasting and dynamic index of insulin-resistance and secretion were calculated. Plasma leptin levels were assessed in 75 children and adolescents.
Results: 434 subjects (210 girls) were enrolled, of whom 320 were G-allele carriers and 114 were homozygous for the C (leptin lowering) allele. Subjects were divided in two groups according to rs10487505 recessive inheritance (CC vs GG/GC). We did not observed differences in anthropometric parameters and obesity age of onset between groups. CC group showed significantly higher fasting insulin levels (P=0.01), higher HOMA-IR (homeostasis model assessment of insulin-resistance, P=0.01), lower WBISI (whole-body insulin sensitivity index, P=0.02), and lower DI (disposition index, P=0.03). Moreover, CC patients showed higher prevalence of prediabetes (9.3% vs 3.4%, P=0.04) and a 2.9-fold (95% CI 1.1-7.9, P=0.04) higher risk of prediabetes compared to G-carriers independently from confounders. Leptin plasma levels were significantly lower in CC group (P=0.03). Hormone levels correlated with Z-score BMI (r=0.25, P=0.04), fasting insulin (r=-0.30, P=0.01), HOMA-IR (r=-0.34, P=0.005), WBISI (r=0.35, P=0.004), and DI (r=0.34, P=0.007).
Main Conclusion: the lncOb rs10487505 variant affects leptin circulating levels and appears to worsen insulin-resistance and heighten the risk of prediabetes in children and adolescents with obesity.
15 Sep 2022 - 17 Sep 2022