Mitochondrial signatures of infant mesenchymal stem cells predict child adiposity: The Healthy Start Study.

IMPORTANCE

Although obesity risk is multifactorial, identification of molecular pathways at birth may reveal early-life susceptibility, guiding prevention and intervention efforts.

OBJECTIVE

We measured transcriptional and DNA methylation profiles of umbilical cord-derived mesenchymal stem cells (MSCs), which are progenitors for body composition (e.g., adipose, muscle), and tested associations with childhood adiposity over the first 4-6yr of life.

DESIGN

Among 140 mother/child dyads enrolled in The Healthy Start Cohort Study, MSCs were isolated at birth and analyzed for their transcriptomic (RNAseq) and DNA methylation profile (Illumina EPIC). We measured newborn (24-72hrs after birth, n=134), infant (4-6mo, n=128), and early childhood (4-6yr, n=81) adiposity (%fat mass [%FM]) with air displacement plethysmography. A parallel in vitro adiposity phenotype was modeled as triglyceride accumulation during MSC adipogenesis.

SETTING

Prenatal obstetrics clinics at the University of Colorado Hospital in 2010-2014. Follow-up of women and children is ongoing.

PARTICIPANTS

Singleton infants born to healthy women across the BMI spectrum.

EXPOSURE: Newborn MSC transcriptome.

MAIN OUTCOME: Infant/childhood adiposity (%FM).

RESULTS

302 MSC transcripts were associated with %FM at birth, infancy and early childhood (p=5, p=296 and p=1), respectively [false discovery rate, FDR<0.05]). Geneset Enrichment Analysis of transcriptome data revealed 670 pathways associated with %FM (FDR<0.05, p=3 at birth, p=267 infancy, p=400 early childhood). Gene sets involved in extracellular matrix organization, were positively associated, while mitochondrial fatty acid beta-oxidation, the citric acid (TCA) cycle, cell cycle and chromosome/telomere maintenance were negatively associated with adiposity at 4-6mo and 4-6yr (FDR<0.05). Mitochondrial complex I pathways downregulation was associated with higher in vivo adiposity at all three timepoints (FDR<0.05), and with in vitro adiposity (p<0.05). We examined shared core enrichment genes between infant and early childhood pathways (p=664), as input for targeted methylation analysis. Of these shared genes, DNA methylation in four CpGs (FDR<0.2) and one noteworthy gene region, HDAC4 (FDR=0.055), associated with %FM in infancy and early childhood, respectively.

CONCLUSIONS AND RELEVANCE: Newborn MSC transcriptomic and methylation features, particularly within mitochondrial pathways, were associated with adiposity through early childhood. These findings suggest that early-life mitochondrial signatures may predict biological susceptibility to greater fat mass accretion.