Low Vitamin B12 in Pregnancy Is Associated With Adipose-Derived Circulating miRs Targeting PPARγ and Insulin Resistance
Low Vitamin B12 in Pregnancy Is Associated With Adipose-Derived Circulating miRs Targeting PPARγ and Insulin Resistance
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DOI：
10.1210/jc.2017-01155
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发表时间：
2017-11-01
影响因子：
5.8
通讯作者：
Saravanan, Ponnusamy
中科院分区：
文献类型：
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作者：
Adaikalakoteswari, Antonysunil;Vatish, Manu;Saravanan, Ponnusamy
背景：妊娠期低维生素B12与孕妇肥胖、胰岛素抵抗（IR）和妊娠期糖尿病相关。B12是单碳代谢的关键辅助因子。目的：我们假设B12在脂肪细胞分化过程中通过改变循环microrna （miRs）在表观遗传调控中发挥作用，并导致不良的代谢表型。设计、设置和主要结果测量：人前脂肪细胞系（Chub-S7）在不同的B12浓度下分化：对照（500 nM）、低B12 （0.15 nM）和无B12 （0 nM）。分娩时采集母体血液（n = 91）和皮下脂肪组织（n = 42）。检测血清B12、叶酸、血脂、血浆单碳代谢物、miR谱、miR表达和基因表达。结果：我们的体外模型表明，b12缺乏条件下的脂肪细胞积累了更多的脂质，具有更高的甘油三酯水平，并且增加了脂肪生成和脂肪生成的基因表达。MiR阵列筛选发现133个涉及多种代谢途径的miRs差异表达（调整后P < 0.05）。在与脂肪细胞分化和脂肪细胞功能相关的12个miR中观察到miR表达改变。在低B12孕妇中验证这些数据证实了脂肪生成和脂肪生成基因的表达增加，SAT中的miRs改变，循环中12种miRs中的11种水平改变。在对其他可能的混杂因素进行校正后，多元回归分析显示B12与体重指数（β: -0.264； 95%可信区间，-0.469至-0.058;P = 0.013）存在独立关联，并由四种靶向过氧化物酶体增殖体激活受体γ和IR的循环miRs介导。结论：妊娠期低B12水平改变了脂肪来源的循环mir，这可能介导脂肪生成和IR表型，导致肥胖。
Context: Low vitamin B12 during pregnancy is associated with higher maternal obesity, insulin resistance (IR), and gestational diabetes mellitus. B12 is a key cofactor in one-carbon metabolism.Objective: We hypothesize that B12 plays a role in epigenetic regulation by altering circulating microRNAs (miRs) during adipocyte differentiation and results in an adverse metabolic phenotype.Design, Settings, and Main Outcome Measure: Human preadipocyte cell line (Chub-S7) was differentiated in various B12 concentrations: control (500 nM), low B12 (0.15 nM), and no B12 (0 nM). Maternal blood samples (n = 91) and subcutaneous adipose tissue (SAT) (n = 42) were collected at delivery. Serum B12, folate, lipids, plasma one-carbon metabolites, miR profiling, miR expression, and gene expression were measured.Results: Our in vitro model demonstrated that adipocytes in B12-deficient conditions accumulated more lipids, had higher triglyceride levels, and increased gene expression of adipogenesis and lipogenesis. MiR array screening revealed differential expression of 133 miRs involving several metabolic pathways (adjusted P < 0.05). Altered miR expressions were observed in 12 miRs related to adipocyte differentiation and function in adipocytes. Validation of these data in pregnant women with low B12 confirmed increased expression of adipogenic and lipogenic genes and altered miRs in SAT and altered levels of 11 of the 12 miRs in circulation. After adjustment for other possible confounders, multiple regression analysis revealed an independent association of B12 with body mass index (beta: -0.264; 95% confidence interval, -0.469 to -0.058; P = 0.013) and was mediated by four circulating miRs targeting peroxisome proliferator-activated receptor gamma and IR.Conclusions: Low B12 levels in pregnancy alter adipose-derived circulating miRs, which may mediate an adipogenic and IR phenotype, leading to obesity.