An individual participant data meta-analysis on metabolomics profiles for obesity and insulin resistance in European children

Christian Hellmuth,Anja Moß,Franca F Kirchberg,Veit Grote,Viola Walter,Elvira Verduci,Pascale Poncelet,Piotr Socha,Elisabeth Thiering,Jean Paul Langhendries ,Hermann Brenner,Dietrich Rothenbacher,Marie Standl,Irina Lehmann,Joaquín Escribano ,Stephanie Brandt,Joachim Heinrich,Dariusz Gruszfeld,Olaf Uhl,Ricardo Closa‐Monasterolo ,Benedetta Mariani,Verònica Luque ,Berthold Koletzko,Martin Wabitsch

doi:10.1038/s41598-019-41449-x

Abstract

Childhood obesity prevalence is rising in countries worldwide. A variety of etiologic factors contribute to childhood obesity but little is known about underlying biochemical mechanisms. We performed an individual participant meta-analysis including 1,020 pre-pubertal children from three European studies and investigated the associations of 285 metabolites measured by LC/MS-MS with BMI z-score, height, weight, HOMA, and lipoprotein concentrations. Seventeen metabolites were significantly associated with BMI z-score. Sphingomyelin (SM) 32:2 showed the strongest association with BMI z-score (P = 4.68 × 10−23) and was also closely related to weight, and less strongly to height and LDL, but not to HOMA. Mass spectrometric analyses identified SM 32:2 as myristic acid containing SM d18:2/14:0. Thirty-five metabolites were significantly associated to HOMA index. Alanine showed the strongest positive association with HOMA (P = 9.77 × 10−16), while acylcarnitines and non-esterified fatty acids were negatively associated with HOMA. SM d18:2/14:0 is a powerful marker for molecular changes in childhood obesity. Tracing back the origin of SM 32:2 to dietary source in combination with genetic predisposition will path the way for early intervention programs. Metabolic profiling might facilitate risk prediction and personalized interventions in overweight children.

Highlights

Childhood obesity prevalence is rising in countries worldwide
Several cross-sectional studies have screened for associations between metabolites and obesity as well as insulin resistance (IR) in adults, but only very few studies exist in childhood obesity and diabetes[9,10,11,12,13,14,15] which were often conducted with small sample sizes of less than 100 children[16] resulting in limited statistical power and a high margin of error
Regarding homeostasis model assessment (HOMA), we found that glutamine (P = 0.013/0.003) as well as non-esterified fatty acids (NEFA) 26:1 (P = 0.012/0.015), 26:2 (P = 0.002/0.01), 26:3 (P = 0.009/0.015) at age 5.5 years were significantly associated with HOMA indices at 8 years in both the unadjusted and adjusted linear model

Summary

Introduction

Childhood obesity prevalence is rising in countries worldwide. A variety of etiologic factors contribute to childhood obesity but little is known about underlying biochemical mechanisms. Several cross-sectional studies have screened for associations between metabolites and obesity as well as insulin resistance (IR) in adults, but only very few studies exist in childhood obesity and diabetes[9,10,11,12,13,14,15] which were often conducted with small sample sizes of less than 100 children[16] resulting in limited statistical power and a high margin of error This is especially limiting in the case of metabolomics data that require statistical adjustment for multiple testing. The follow-up visits at 5.5 and 8 years of age of the CHOP children allowed for a longitudinal and a predictive analysis of our targeted metabolome

Methods

Results

Discussion

Conclusion