Hepatic fat is a stronger correlate of key clinical and molecular abnormalities than visceral and abdominal subcutaneous fat in youth

Introduction Body fat distribution is strongly associated with cardiometabolic disease (CMD), but the relative importance of hepatic fat as an underlying driver remains unclear. Here, we applied a systems biology approach to compare the clinical and molecular subnetworks that correlate with hepatic fat, visceral fat, and abdominal subcutaneous fat distribution. Research design and methods This was a cross-sectional sub-study of 283 children/adolescents (7–19 years) from the Yale Pediatric NAFLD Cohort. Untargeted, high-resolution metabolomics (HRM) was performed on plasma and combined with existing clinical variables including hepatic and abdominal fat measured by MRI. Integrative network analysis was coupled with pathway enrichment analysis and multivariable linear regression (MLR) to examine which metabolites and clinical variables associated with each fat depot. Results The data divided into four communities of correlated variables (|r|>0.15, pConclusions These data-driven findings show a stronger association of hepatic fat with key CMD risk factors compared with abdominal fats. The molecular network identified using HRM that associated with hepatic fat provides insight into potential mechanisms underlying the hepatic fat–insulin resistance interface in youth.
Funding Information
  • NIH Office of the Director (S10-OD018006)
  • National Institute of Environmental Health Sciences (P30-ES019776, U2C-ES026560)
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30DK111024, R01-DK111038, R01-DK114504)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (R21-HD028016, R21-HD089056)

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