Antonysunil Adaikalakoteswari1, Manu Vatish2, Mohammad Tauqeer Alam3, Sascha Ott3, Sudhesh Kumar1,4, Ponnusamy Saravanan1,5. 1. Warwick Medical School, University of Warwick, Warwick CV2 2DX, United Kingdom. 2. Nuffield Department of Obstetrics & Gynaecology, University of Oxford, Oxford OX3 9DU, United Kingdom. 3. Department of Computer Science, University of Warwick, Warwick CV4 7AL, United Kingdom. 4. University Hospital of Coventry and Warwickshire, Coventry CV2 2DX, United Kingdom. 5. Academic Department of Diabetes and Metabolism, George Eliot Hospital, Nuneaton CV10 7DJ, United Kingdom.
Abstract
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 (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. Conclusions: Low B12 levels in pregnancy alter adipose-derived circulating miRs, which may mediate an adipogenic and IR phenotype, leading to obesity.
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 (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. Conclusions: Low B12 levels in pregnancy alter adipose-derived circulating miRs, which may mediate an adipogenic and IR phenotype, leading to obesity.
Authors: Bambarendage P U Perera; Rachel K Morgan; Katelyn M Polemi; Kimmie E Sala-Hamrick; Laurie K Svoboda; Dana C Dolinoy Journal: Curr Environ Health Rep Date: 2022-08-02