Maternal obesity alters fatty acid oxidation, AMPK activity, and associated DNA methylation in mesenchymal stem cells from human infants

Abstract

ObjectiveInfants born to mothers with obesity have greater adiposity, ectopic fat storage, and are at increased risk for childhood obesity and metabolic disease compared with infants of normal weight mothers, though the cellular mechanisms mediating these effects are unclear.MethodsWe tested the hypothesis that human, umbilical cord-derived mesenchymal stem cells (MSCs) from infants born to obese (Ob-MSC) versus normal weight (NW-MSC) mothers demonstrate altered fatty acid metabolism consistent with adult obesity. In infant MSCs undergoing myogenesis in vitro, we measured cellular lipid metabolism and AMPK activity, AMPK activation in response to cellular nutrient stress, and MSC DNA methylation and mRNA content of genes related to oxidative metabolism.ResultsWe found that Ob-MSCs exhibit greater lipid accumulation, lower fatty acid oxidation (FAO), and dysregulation of AMPK activity when undergoing myogenesis in vitro. Further experiments revealed a clear phenotype distinction within the Ob-MSC group where more severe MSC metabolic perturbation corresponded to greater neonatal adiposity and umbilical cord blood insulin levels. Targeted analysis of DNA methylation array revealed Ob-MSC hypermethylation in genes regulating FAO (PRKAG2, ACC2, CPT1A, SDHC) and corresponding lower mRNA content of these genes. Moreover, MSC methylation was positively correlated with infant adiposity.ConclusionsThese data suggest that greater infant adiposity is associated with suppressed AMPK activity and reduced lipid oxidation in MSCs from infants born to mothers with obesity and may be an important, early marker of underlying obesity risk.

Insight into the development of obesity: functional alterations of adipose‐derived mesenchymal stem cells

“…More interestingly, maternal obesity and increased neonatal adiposity correspond with altered metabolism of umbilical cord‐derived MSC (uMSC) from human infants . The authors demonstrate further that maternal obesity changes fatty acid oxidation, AMP‐activated protein kinase activity and associated DNA methylation in infant uMSCs , suggesting that altered uMSCs are crucial for the development of offspring obesity. These data, in combination with the observations from obese ASCs, highlight that obesity is tightly connected with functional alterations and impairments of various stem/progenitor cells.…”

AMP-activated protein kinase: the current landscape for drug development

“…The findings that AMPK activation promotes fatty acid oxidation, mitochondrial function, autophagy and skeletal muscle glucose uptake, while suppressing inflammation as well as fatty acid and cholesterol synthesis, provides a strong rationale for therapeutic targeting. Notably, AMPK activity is lower in mesenchymal stem cells from human infants born from obese mothers 187 , an effect that is also observed in multiple tissues of individuals with obesity and insulin resistance 188 . Importantly, these reductions in AMPK are largely restored with treatments that exert beneficial metabolic effects such as endurance exercise, caloric restriction and bariatric surgery, suggesting that AMPK may play an important role in mediating these effects 188 .…”

The effects of obesity on skeletal muscle contractile function

“…The obesity-induced suppression of AMPK activity may even be transferred between mother and offspring. Mesenchymal stem cells, which give rise to muscle cells and adipocytes, of human infants born to obese mothers have lower AMPK activity compared with those of infants from normal weight mothers (Du et al, 2010;Boyle et al, 2017).…”