Background: Leptin, primarily secreted by adipocytes, is a pivotal signal of the body's energy status and exhibits pleiotropic effects. Homozygous mutations in the leptin gene which result in defective synthesis, release or bioactivity, cause intense hyperphagia and early-onset severe obesity, along with multiple metabolic, hormonal, and immunological abnormalities. In vitro and animal model studies suggest that leptin plays a role in linear growth. So far, this has not been fully investigated in humans.
Objective: To evaluate IGF-1 serum levels and growth before and after 12 months of leptin replacement therapy in patients with congenital leptin deficiency (CLD).
Patients and Methods: This case-series contains n=9 patients (6 males) with CLD due to defective production (n=5) or bioinactive leptin (n=4). We retrospectively analysed data regarding age, height-SDS, BMI-SDS, IGF-1-SDS, IGFBP3-SDS, IGF-1/IGFBP3 ratio-SDS at the beginning (T0), after 6 months (T6) and after 12 months (T12) of leptin replacement therapy.
Results: At baseline, mean age was 8.2±5.4 yrs (range: 0.9-14.8 yrs), mean BMI-SDS was +4.1±1.4 (range:2.3-6.0) and IGF-1-SDS as well as IGF-1/IGFBP3 ratio-SDS were negative in all patients (IGF-1-SDS T0:-1.16±0.83, IGF-1/IGFBP3 ratio-SDS T0:-1.10±0.80). Mean IGFBP3-SDS was 0.17±1.36. Leptin replacement resulted in a reduction of BMI-SDS of 1.40±0.81 after 12 months. During leptin replacement therapy, IGF1-SDS increased from T0:-1.16±0.83 to T6:-0.22±1.81 and to T12:+0.26±1.26. We also observed an increase in IGFBP3-SDS and in IGF-1/IGFBP3 ratio-SDS (ΔT0-T12IGFBP3-SDS=+0.67±0.95, ΔT0-T12IGF-1/IGFBP3 ratio-SDS=+1.16±1.81). Mean change in height-SDS under leptin replacement therapy was not significant; however, when we looked at the individual data, we observed that all children younger than 12 yrs (n=5) showed a positive change (0.12-0.64).
Conclusions: Most studies show that obese children have normal or increased IGF-1 levels, and it is known that IGF-1 levels decrease under caloric restriction (Hawkes and Grimberg, Pediatr Endocrinol Rev. 2015;13(2):499-511). Interestingly, we found that IGF-1 serum levels in severely obese CDL children were low at baseline and increased during metreleptin substitution despite reduced caloric intake. We also observed an acceleration of growth in children <12yo. Our findings support the hypothesis that leptin, as a signal of the energy status, promotes IGF-1 production and growth.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology