Section of Nutrition, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA.
Section of Nutrition, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA.
Mol Metab. 2017 Nov;6(11):1503-1516. doi: 10.1016/j.molmet.2017.08.012. Epub 2017 Sep 1.
Infants 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.
We 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.
We 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.
These 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.
与正常体重母亲所生婴儿相比，肥胖母亲所生婴儿脂肪含量更高，异位脂肪储存更多，并且在儿童时期肥胖和代谢疾病的风险增加，尽管介导这些影响的细胞机制尚不清楚。
我们检验了这样一个假设，即肥胖（Ob-MSC）与正常体重（NW-MSC）母亲的人脐带间充质干细胞（MSCs）在体外成肌过程中表现出与成人肥胖一致的改变脂肪酸代谢。我们测量了细胞脂质代谢和 AMPK 活性、细胞营养应激下 AMPK 的激活以及 MSC DNA 甲基化和与氧化代谢相关基因的 mRNA 含量。
我们发现 Ob-MSCs 在体外成肌过程中表现出更大的脂质积累、更低的脂肪酸氧化（FAO）和 AMPK 活性失调。进一步的实验表明，Ob-MSC 组内存在明显的表型差异，其中更严重的 MSC 代谢紊乱与新生儿脂肪量和脐血胰岛素水平更高相对应。针对 DNA 甲基化阵列的靶向分析显示，调节 FAO 的基因（PRKAG2、ACC2、CPT1A、SDHC）在 Ob-MSC 中出现超甲基化，并且这些基因的 mRNA 含量降低。此外，MSC 甲基化与婴儿肥胖呈正相关。
这些数据表明，与正常体重母亲所生婴儿相比，肥胖母亲所生婴儿的脂肪含量更高，并且在肥胖母亲所生婴儿的 MSCs 中 AMPK 活性降低和脂质氧化减少，这可能是潜在肥胖风险的重要早期标志物。
