Inversed impaired osteogenic activity in children with severe obesity due to MC4R deficiency compared to LEP and LEPR deficiency
Children with MC4R deficiency show higher bone formation markers compared to those with LEP and LEPR deficiencies, indicating differing impacts of genetic obesity on bone health.
Where it sits
this study against the rest of the setmelanotide corpusSummary and findings
This study measured bone turnover and metabolic biomarkers in children with severe obesity due to biallelic loss-of-function variants in the LEP, LEPR, or MC4R genes. A total of 41 children with severe obesity and 28 age-matched controls were included. Significant differences in serum levels of osteocalcin and osteopontin were observed among the groups.
Abstract
<title>Abstract</title> <p> <bold>OBJECTIVE</bold> Chronic obesity is associated with impaired bone health. However, few investigations have been conducted to assess bone physiology in early-onset obesity. In this study, we measured specific bone turnover and metabolic biomarkers in children with severe obesity with biallelic loss-of-function variants of the leptin ( <italic>LEP)</italic> , leptin receptor <italic>(LEPR)</italic> , or melanocortin 4 receptor ( <italic>MC4R)</italic> genes. <bold>METHODS</bold> Forty-one children aged 0.3–13 years with a BMI SDS ≥ 3, previously identified with pathogenic variants in <italic>LEP</italic> , <italic>LEPR</italic> , or <italic>MC4R</italic> , were recruited for the current study. Additionally, 13 age-matched children with severe obesity who tested negative for variants in known obesity-related genes were included, and another 15 unrelated age-matched children with normal body weight served as the control group. Serum osteocalcin, osteopontin, osteoprotegerin, and sclerostin levels were assessed using multi-analyte profiling. Serum leptin, insulin, and cortisol levels were determined using ELISA. <bold>RESULTS</bold> Serum levels of osteocalcin and osteopontin, specific markers of bone formation, were significantly lower in subjects with <italic>LEP</italic> and <italic>LEPR</italic> biallelic variants than in the control group. In contrast, the values of these two biomarkers in subjects with <italic>MC4R</italic> deficiency were significantly higher than those in the other groups. No differences were observed in the bone resorption markers osteoprotegerin and sclerostin. Hyperleptinemia was more pronounced in subjects with <italic>LEPR</italic> deficiency. Serum insulin concentrations were elevated in subjects with <italic>MC4R</italic> deficiency, whereas serum cortisol levels were significantly higher in subjects with <italic>LEP</italic> deficiency than in all other groups. <bold>CONCLUSION</bold> Our data demonstrate that osteogenic activity (but not resorption activity) is differentially affected in children with complete genetic disruption of the leptin signaling pathway. Children with <italic>MC4R</italic> deficiency showed higher osteogenic markers, but children with <italic>LEP</italic> and <italic>LEPR</italic> deficiencies showed the opposite. Our results support the usefulness of bone turnover biomarkers for the assessment and management of bone health in different types of obesity. </p>