Maternal High Folic Acid Supplement Promotes Glucose Intolerance and Insulin Resistance in Male Mouse Offspring Fed a High-Fat Diet

Abstract

Maternal nutrition may influence metabolic profiles in offspring. We aimed to investigate the effect of maternal folic acid supplement on glucose metabolism in mouse offspring fed a high-fat diet (HFD). Sixty C57BL/6 female mice were randomly assigned into three dietary groups and fed the AIN-93G diet containing 2 (control), 5 (recommended folic acid supplement, RFolS) or 40 (high folic acid supplement, HFolS) mg folic acid/kg of diet. All male offspring were fed HFD for eight weeks. Physiological, biochemical and genetic variables were measured. Before HFD feeding, developmental variables and metabolic profiles were comparable among each offspring group. However, after eight weeks of HFD feeding, the offspring of HFolS dams (Off-HFolS) were more vulnerable to suffer from obesity (p = 0.009), glucose intolerance (p < 0.001) and insulin resistance (p < 0.001), compared with the controls. Off-HFolS had reduced serum adiponectin concentration, accompanied with decreased adiponectin mRNA level but increased global DNA methylation level in white adipose tissue. In conclusion, our results suggest maternal HFolS exacerbates the detrimental effect of HFD on glucose intolerance and insulin resistance in male offspring, implying that HFolS during pregnancy should be adopted cautiously in the general population of pregnant women to avoid potential deleterious effect on the metabolic diseases in their offspring.

Folic Acid Supplement Intake in Early Pregnancy Increases Risk of Gestational Diabetes Mellitus: Evidence From a Prospective Cohort Study

“…GDM was diagnosed in 249 of the 1,938 (12.8%) women. We found that daily FA supplement consumption in the first trimester was associated with an increased risk of GDM (adjusted odds ratio [ 2 and not taking any FA supplements. An increased risk of GDM was not apparent for women using FA before pregnancy alone or in the second trimester alone.…”

“…In addition, animal experiments have reported that maternal high-FA supplement promotes glucose intolerance and insulin resistance in male mouse offspring fed a high-fat diet (2). However, whether FA supplement consumption preconception and during pregnancy increases the risk of GDM has not yet been investigated.…”

Maternal folic acid consumption during gestation and its long-term effects on offspring's liver: a systematic review

“…1 Suitable diet consumption during gestation is worthwhile for normal developing of offsprings and may determine their metabolic and hormonal status at adulthood. 2,3 It was stated that nutritional imbalance during critical periods, such as gestation, may predispose to diseases at adulthood.…”

Epigenetics and Metabolism

“…23 The importance of dietary methyl donors to epigenetic regulation has been examined in rodent models as well as in humans, 23 and the effects of maternal dietary intake are a key focus of recent studies. 24,25 How the enzymes responsible for individual modification patterns interrelate has been the subject of recent studies. 26 For example, competition for available SAM may regulate the contrasting events associated with transcriptionally permissive methyl-H3K4 modifications and repressive methyl-H3K9 or methyl-CpG modifications.…”

“…201 By contrast, the deleterious effects of maternal HFD on glucose intolerance and insulin resistance were exacerbated by folic acid supplementation, concurrent with increased global DNA methylation in mouse adipose tissue. 25 The effects of maternal folate diet are complicated and require further study, with both low and high folate intake associated with increased disease risk in adult offspring. 15 For instance, standard recommended maternal daily intake of 0.4 mg/d was associated with lower birth weight and altered DNA methylation of IGF2.…”