Background: Low vitamin B12 (B12) during pregnancy is associated with higher maternal obesity, insulin resistance (IR) and gestational diabetes (GDM). However, it is not clear whether these are causally related.
Objective: B12 is a key co-factor of the DNA methylation cycle (1-carbon metabolism). We hypothesize that B12 plays a role in epigenetic regulation by altering circulating miRNAs (miRs) during adipocyte differentiation and results in an adverse metabolic phenotype.
Methods: Maternal venous blood samples (n=91) and subcutaneous adipose tissue (n=42) were collected at delivery. Human pre-adipocyte cells (Chub-S7) were differentiated in various B12 concentrations (1) Control: (B12=500nM); (2) LowB12 (B12=0.15nM) (3) NoB12: (B12=0nM). Serum B12, folate, lipids and plasma 1-carbon metabolites were determined. miR profiling, miR expression and gene expression were measured.
Results: We demonstrated that low B12 in human pregnancy was associated with higher BMI and in maternal adipose tissue, increased expression of adipogenic and lipogenic genes. Our in vitro human adipocyte model showed that adipocytes differentiated in B12 deficient conditions accumulated more lipids, had higher triglyceride levels and increased adipogenesis and lipogenesis. MiR array screening revealed differential expression of 133 miRs. We then validated 12 miRs related to adipocyte differentiation and function. MiRs targeting PPARγ (miR-27b, miR-23a, miR-130b), CEBPα (miR-31), adipocyte differentiation (miR-143, miR-145, miR-146a, miR-221, miR-222, miR-125b) and IR (miR-103a, miR-107) were altered in adipocytes and its secretion. In vivo validation in pregnant women with low B12 confirmed a similar pattern of altered miR expression in human adipose tissue and circulating miR expression in serum. After adjusting for likely confounders, multiple regression analysis revealed an independent association of B12 with BMI and was mediated by altered circulating miRs targeting PPARγ (miR-27b, miR-23a) and IR (miR-103a, miR-107).
Conclusions: Our study shows that low B12 levels in pregnancy alters adipose derived circulating miRs, which may mediate an adipogenic and insulin resistant phenotype leading to obesity.