IMPE Abstracts

Background: The leptin-melanocortin pathway regulates satiety and energy metabolism. Prohormone-convertase-1 (PCSK1) cleavage of hypothalamic proopiomelanocortin is an essential step in central leptin signaling and effects. The heterozygous N221D variant in PCSK1 is considered to increase obesity risk in humans through the decrease in enzymatic activity and/or loss of resilience to stressors and could also influence its role in proinsulin processing.

Objectives: To explore the prevalence of the heterozygous N221D variant in PCSK1 in 1066 children and adolescents with obesity and to compare their clinical and metabolic features with those in patients without identified genetic variants.

Patients and methods: A transversal study of 1066 patients below 18 years of age with obesity (BMI >+2 SDS, 48.6% females; 54.4% prepubertal; 71.5% Caucasians; age: 10.38±3.44 years, BMI: +4.38±1.77 SDS) was carried-out and next generation sequencing (NGS) analysis of 17 genes involved in the leptin-melanocortin pathway (CREBBP, CPE, HTR2C, KSR2, LEP, LEPR, MAGEL2, MC3R, MC4R, MRAP2, NCOA1, PCSK1, POMC, SH2B1, SIM1, TBX3 and TUB) was performed. Newborn anthropometry, age at obesity onset and at first evaluation, height-SDS, BMI-SDS, glucose and lipid metabolism parameters were compared between patients carrying the N221D variant in PCSK1 in heterozygosis and those with no variants found in any of the studied genes.

Results: A total of 532 patients (49.9%) carried at least one heterozygous variant in the 17 selected genes, 68 patients (6.4%, 30 females/38 males) carried the N221D variant in PCSK1 (26 of them in combination with at least one variant in another of the other genes studied). Patients carrying the N221D variant in PCSK1 (n=68) showed significantly lower triglyceride levels (72.38±41.53 vs. 89.19±54.33 mg/dl; P<0.05) and a trend towards lower insulin levels (13.83±8.97 vs. 16.00±8.62 mg/dl; P=0.06) than patients with no variant in the studied genes (n=531). When the comparison was restricted to the 42 patients exclusively carrying the N221D variant in PCSK1 (without any variant in the remaining genes studied), they showed significantly lower insulin (12.55±5.95 vs. 16.00±8.62 mg/dl; P<0.05) and HOMA (2.86±1.42 vs. 3.63±2.06 mg/dl; P<0.05) than patients with no variant in the studied genes.

Conclusions: 1) The prevalence of the N221D variant in PCSK1 in heterozygosity in childhood obesity is high in our environment. 2) The metabolic profile in these patients could be influenced by a certain degree of impairment of PCSK1 mediated cleavage of proinsulin to insulin.