Melanocortin-4 Receptor and Lipocalin 2 Gene Variants in Spanish Children with Abdominal Obesity: Effects on BMI-SDS after a Lifestyle Intervention

Abstract

Mutations leading to a reduced function of the melanocortin-4 receptor (MC4R) exert a major gene effect on extreme obesity. Recently it was shown that the bone derived hormone lipocalin 2 (LCN2) binds to the MC4R and activates a MC4R dependent anorexigenic pathway. We identified mutations in both genes and screened the effects of MC4R and LCN2 mutations on eating behavior and weight change after a lifestyle intervention. One hundred and twelve children (11.24 ± 2.6 years, BMI-SDS 2.91 ± 1.07) with abdominal obesity participated in a lifestyle intervention. MC4R and LCN2 coding regions were screened by Sanger sequencing. Eating behavior was assessed at baseline with the Children Eating Behavior Questionnaire (CEBQ). We detected three previously described non-synonymous MC4R variants (Glu42Lys, Thr150Ile, and Arg305Gln) and one non-synonymous polymorphism (Ile251Leu). Regarding LCN2, one known non-synonymous variant (Thr124Met) was detected. Eating behavior was described in carriers of the MC4R and LCN2 mutation and in non-carriers. MC4R and LCN2 mutations were detected in 2.42% and 0.84%, respectively, of Spanish children with abdominal obesity. A number of subjects with functional mutation variants in MC4R and LCN2 were able to achieve a reduction in BMI-SDS after a lifestyle intervention.

Obesity treatment effect in Danish children and adolescents carrying Melanocortin-4 Receptor mutations

“…In our cohort of children and adolescents with overweight or obesity, we identified 30 carriers of damaging or unresolved MC4R mutations (2.5%). Our finding is similar to the previously reported prevalence of 2.5% in a sample of Danish men with juvenile-onset obesity [ 35 ], and is in accordance with other studies in samples of European individuals with obesity reporting prevalences between 0.2 and 6.3% [ 8 , 11 , 13 , 15 , 17 , 18 , 36 , 44 ]. In comparison, the prevalence of pathogenic MC4R mutations has been estimated to be 0.15% in the general German population [ 36 ], and a similar prevalence would be expected in the Danish population.…”

“…In both studies, no significant differences in other-examined traits were identified [ 16 , 17 ]. Finally, a Spanish study described that among children with obesity, carriers of MC4R mutations (n = 8) achieved similar or greater reduction in BMI-SDS loss compared to noncarriers ( n = 103) after a short 8-week lifestyle intervention [ 18 ]. However, only some of the carriers maintained the reduction in BMI SDS after 1 year of intervention [ 18 ].…”

“…Few studies investigated the possible differences in response to obesity treatment between MC4R mutation carriers and noncarriers in children. Generally, the mutations do not seem to influence the effect of lifestyle interventions [ 16 – 18 ], though carriers of an MC4R mutation may have difficulties maintaining their weight loss [ 16 ]. These intervention studies have been limited by small study samples and short duration.…”

Obesity treatment effect in danish children and adolescents carrying melanocortin-4 receptor mutations

“…Few studies investigated the possible differences in response to obesity treatment between MC4R mutation carriers and noncarriers in children. Generally, the mutations do not seem to influence the effect of lifestyle interventions [16][17][18], though carriers of an MC4R mutation may have difficulties maintaining their weight loss [16]. These intervention studies have been limited by small study samples and short duration.…”

Dietary Behavior and Physical Activity in Children and Adolescents

“…The diverse articles in this Special Issue highlight the complexity and extent to which nutrition and physical activity behaviors may influence different health aspects of children and adolescents. Few studies in this Special Issue combined genetic data with nutritional data [28], a likely expanding research area in the coming years, with the goal to provide personalized and gene-based dietary recommendations in the future. As seen by the various findings and recommendations, not only is more work in this area required but the translation of this work to practice and policy is imperative if we are to address the challenges impacting the nutrition, physical activity, and health of young populations.…”