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REPRODUCTIVE HEALTH

Maternal Obesity Overview

The Role of 1C Metabolism in Maternal Obesity

 

Highlights

  • In a study of 4243 women with singleton pregnancies in the Netherlands, plasma folate and vitamin B12 were significantly lower at 12-15 weeks of pregnancy in women overweight or obese prior to becoming pregnant than women of normal weight (BMI = 18.5-24.9 kg/m2). 1 This finding was confirmed in a second study of 498 women in the UK that examined the relationship between blood levels of folate and vitamin B12 and maternal weight (BMI) in early pregnancy (defined as first visit following sonographic confirmation of an ongoing pregnancy). 2
  • Pre-pregnancy BMI for 2797 women in Norway was found to be negatively correlated with plasma folate, vitamins B6 and B12 at 18 weeks of pregnancy, but positively correlated with two markers of cellular inflammation, neopterin and KTR (kynurenine/tryptophan ratio). 3 Total homocysteine was also negatively correlated with folate and vitamin B12.
  • BMI was recorded for 995 women in the UK at 28 weeks gestation along with assessments for serum vitamin B12, folate, HOMA-IR (homeostatic model assessment of insulin resistance), triglycerides and aspartate aminotransferase (AST), the latter three variables markers of adiposity/body fat metabolism. 4 In univariate statistical models, both vitamin B12 and folate were negatively correlated with BMI, HOMA-R, glucose, and triglycerides, but positively correlated with AST. In multivariate models, however, only vitamin B12 was a significant predictor of BMI (R = -0.15, p = <0.001).  
  • In another UK study, 30 women in early pregnancy who had low vitamin B12 levels, also had significantly higher plasma homocysteine and triglycerides, but lower levels of methionine, SAM and the SAM:SAH ratio (a measure of methylation potential). 5
  • Blood samples were collected from 91 mother-infant pairs at delivery and vitamin B12, folate and homocysteine were measured along with insulin, glucose, triglycerides, LDL and HDL cholesterol. Maternal B12 levels were found to be inversely related to neonatal triglycerides, HOMA-IR and homocysteine, but positively related to HDL cholesterol. 6
  • In a review of data from 46 publications (31,402 pregnancies), maternal high triglycerides and low HDL cholesterol throughout pregnancy were associated with increased birth weight and a greater risk of large-for-gestational-age newborns. 7 The strongest associations were found for women who were overweight or obese prior to pregnancy.  
  • Plasma methionine cycle biomarkers (methionine, homocysteine, betaine, folate, vitamin B12) were assessed in baboons given a normal-diet and those fed a high fat-high energy diet (HF-HED) and their fetuses at 0.9G (Term = 185 days).8 Both HF-HED mothers and fetuses had significantly higher levels of (1) homocysteine and folate than their counterparts given the normal diet, (2) lower levels of vitamin B12 and betaine, and (3) the HF-HED fetuses had lower methionine, while the HF-HED mothers had higher triglycerides and body weight gain prior to pregnancy (5.8 vs 3.1 kg). Elevated levels of folate in the HF-HED mothers and fetuses was thought to be due to low levels of B12 and/or methionine.

Discussion

The observations summarized above have been at least partially confirmed by the most recently published study in this series 9, in which two UK cohorts of 60 and 244 pregnant women, respectively, were assessed at 16-18 weeks of pregnancy for select plasma/serum 1C metabolic parameters. In both cohorts, vitamin B12 was negatively correlated with BMI, homocysteine, and MMA (methylmalonic acid) at a p value ≤ 0.005, and positively correlated with the SAM:SAH ratio. In the 60 subject cohort, B12 was positively correlated with HDL cholesterol, but negatively correlated with triglycerides.

Several studies have been performed that provide insight into the 1C-related biochemical mechanisms underlying obesity. In the first,10 vitamin B12 and several other parameters of 1C status and cholesterol synthesis were measured in the blood of 315 women of reproductive age from the NDNS (National Diet and Nutrition Survey) database in the UK, 152 pregnant women in Saudi Arabia at 16-28 weeks gestation, and 91 women with singleton pregnancies from the University Hospital Coventry and Warwickshire (UHCW) having elective caesarean sections at 37-42 weeks gestation. Women with low levels of B12 (≤190 ng/mL) in all three cohorts had higher concentrations of homocysteine and one or more of the cholesterol parameters that were evaluated (Total-C, LDL-C, Total-C/HDL ratio), and, in the two with pregnant women, B12 and BMI were negatively correlated. Subcutaneous adipose tissue obtained from five UHCW women with normal B12 versus five with low B12 revealed that mRNA expression of the cholesterol regulatory genes SREBF1, SREBF2 and LDLR and the cholesterol biosynthetic gene HMGCR were upregulated in the low B12 mothers. This finding is consistent with results obtained from human adipocytes cultured in the presence of normal (500 nM), low (0.15 nM) or no vitamin B12, in which the latter two groups exhibited significant increases in total cholesterol along with upregulation of numerous genes associated with cholesterol biosynthesis (HMGCR, HMGCS1, IDI1, SQLE, SC4MOL, LDLR, INSIG1, StarD4, SREBP1-2 βactin, SREBF1-2). Interestingly, the reduced expression of mRNAs from these genes in normal B12 adipocyte cultures was accompanied by higher levels of SAM, reduced SAH, and a 2.5 to 3 fold greater SAM:SAH ratio in comparison to the no or low B12 conditions. A reasonable inference from this study is that in the presence of adequate levels of adipocyte vitamin B12, epigenetic control of genes encoding for cholesterol synthesis is maintained through promoter methylation mediated via 1C metabolism. If B12 is too low, then adequate levels of SAM are not available for methylation of the DNA promoters, with a resultant increase in transcriptional activity and associated gene expression.  

In experiments similar to the above,11 adipocytes cultured in the presence of low/no B12, had significantly higher lipid and triglyceride concentrations in comparison to cells grown in a normal B12 environment, accompanied by upregulation of genes associated with adipogenesis (PPARy, CEBPα, RXRα) and lipogenesis (FASN, ACACA, Perilipin), with essentially identical results being obtained with subcutaneous adipose tissue from pregnant women. In low concentrations of B12, 36 microRNAs (post-transcriptional epigenetic regulators) were upregulated and 97 were down regulated, and four of these (miR-27b, miR-23a miR-103a, miR-107) were found to be negatively correlated with BMI along with B12 levels. Indeed, when these four miRs were included separately in multiple regression models with B12, the significance of B12 was reduced from p = 0.013 to <0.105, suggesting that at least some of the effect of B12 on BMI is mediated by miRs.

Conclusion

Women who are overweight/obese prior to or during pregnancy are more likely to have levels of 1C metabolism intermediates, in particular, vitamin B12, that are lower than their normal weight counterparts. Low vitamin B12 is an indicator of an impaired methionine cycle that may be unable to meet the methylation demands of the fertilized egg, or developing embryo/fetus, whose genome is being dynamically expressed. Failure to regulate the transcriptional activity of genes involved in adipogenesis/lipogenesis through either promoter methylation or microRNA synthesis could result in excessive lipid production and predispose the fetus to various neurologic or metabolic disorders in utero and/or later in life (fetal/developmental programming). Give these potential negative consequences, and the known importance of 1C metabolism intermediates in female reproductive health, supplementation with micronutrients that support 1C metabolism may be warranted in women that are overweight/obese and who want to have a baby, or are already pregnant.

References

  1. Scholing JM, Oltho MR, Jonker FAM, et al. Association between pre-pregnancy weight status and maternal micronutrient status in early pregnancy. Pub Health Nutr; 21; 2018: 2046–2055.
  2. O’Malley EG, Reynolds CM E, Cawley S, et al. Folate and vitamin B12 levels in early pregnancy and maternal obesity. Eur J Obst Gyn and Repro Biol. 231; 2018: 80-84.
  3. Bjørke-Monsen AL, Ulvik A, Nilsen RM, et al. Impact of Pre-Pregnancy BMI on B Vitamin and Inflammatory Status in Early Pregnancy: An Observational Cohort Study. Nutrients. 2016; 8: 776.
  4. Knight BA, Shields BM, Brook A, et al. Lower Circulating B12 Is Associated with Higher Obesity and Insulin Resistance during Pregnancy in a Non-Diabetic White British Population. PLoS ONE 10, e0135268 (2015).
  5. Adaikalakoteswari A, Webster C, Goljan I, et al. Simultaneous detection of five one-carbon metabolites in plasma using stable isotope dilution liquid chromatography tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2016; 1012–1013: 186–192.
  6. Adaikalakoteswari A, Vatish M, Lawson A, et al. Low maternal vitamin B12 status is associated with lower cord blood HDL cholesterol in white Caucasians living in the UK. Nutrients. 2015; 7: 2401–2414.
  7. Wang J, Moore D, Subramanian A, et al. Gestational dyslipidaemia and adverse birthweight outcomes: a systematic review and meta-analysis. Obes Rev. 2018; 19: 1256–1268.
  8. Nathanielsz1 PW, Yan J, Green R, et al. Maternal obesity disrupts the methionine cycle in baboon pregnancy. Physiol Rep. 2015;3: , e12564, doi: 10.14814/phy2.12564.
  9. Adaikalakoteswari A, Wood C, Mina TH, et al. Vitamin B12 deficiency and altered one‑carbon metabolites in early pregnancy is associated with maternal obesity and dyslipidaemia. Scientific Reports. 2020;10: 11066.
  10. Adaikalakoteswari A, Finer S, Voyias PD, et al. Vitamin B12 insufficiency induces cholesterol biosynthesis by limiting s-adenosylmethionine and modulating the methylation of SREBF1 and LDLR genes. Clin Epigenetics. 2015; 7: 14.
  11. Adaikalakoteswari, A, Vatish M, Alam MT, et al. Low vitamin B12 in pregnancy is associated with adipose-derived circulating miRs targeting PPARγ and insulin resistance. J Clin Endocrinol Metab. 2017; 102: 4200–4209.

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