Hepatic fat accumulation is often associated with cardiometabolic disease (CMD) risk factors in children, but the mechanism is unclear. We measured untargeted metabolomics in plasma from 219 obese children/adolescents with (37%) and without (63%) fatty liver assessed by magnetic resonance imaging. An integrative network analysis, which involved several steps including pairwise association analyses and a multilevel community detection algorithm, was performed using xMWAS to explore clustering patterns of metabolomics, clinical biomarkers, and abdominal and hepatic fat. This identified 3 communities consisting of significantly correlated variables (|r| > 0.4, p < 0.05) as depicted in Figure 1. Notably, the community featuring hepatic fat clustered with several CMD risk factors, including insulin resistance and dyslipidemia. Pathway analyses of the metabolites in this cluster using mummichog showed enrichment in carnitine shuttle and glycerophospholipid metabolism (p<0.05), including several acyl-carnitine species and linoleic acid. Other metabolites in the cluster were the aromatic and branched chain amino acids tyrosine and isoleucine, respectively. These results suggest that hepatic fat is more closely correlated with CMD risk factors compared to other abdominal fat depots and may offer insights into biological mechanisms that underlie this finding.


C.E. Cioffi: None. K. Narayan: None. K. Uppal: None. B. Pierpont: None. S. Caprio: None. N. Santoro: None. M.B. Vos: Advisory Panel; Self; Intercept Pharmaceuticals, Inc. Board Member; Self; TARGET PharmaSolutions. Consultant; Self; Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Shire. Research Support; Self; Gemphire Therapeutics Inc., Immuron, TARGET PharmaSolutions.


National Institute of Diabetes and Digestive and Kidney Diseases (R01DK111038, T32DK007734, P30DK111024); Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD028016, R21HD089056)

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