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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.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.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.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 (β: -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 γ and IR.Low B12 levels in pregnancy alter adipose-derived circulating miRs, which may mediate an adipogenic and IR phenotype, leading to obesity.

Original publication

DOI

10.1210/jc.2017-01155

Type

Journal article

Journal

The Journal of clinical endocrinology and metabolism

Publication Date

11/2017

Volume

102

Pages

4200 - 4209

Addresses

Warwick Medical School, University of Warwick, Warwick CV2 2DX, United Kingdom.

Keywords

Cells, Cultured, 3T3 Cells, Adipocytes, Animals, Humans, Mice, Pregnancy Complications, Diabetes, Gestational, Insulin Resistance, Vitamin B 12 Deficiency, Obesity, Vitamin B 12, PPAR gamma, Cross-Sectional Studies, Gene Expression Regulation, Pregnancy, Female, Adipogenesis, Circulating MicroRNA