Maternal high folic acid supplement promotes glucose intolerance and insulin resistance in male mouse offspring fed a high-fat diet.

Yifan Huang,Changhao Sun,Yonghan He,Ying Li,Xiaowei Sun,Yujie He

doi:10.3390/ijms15046298

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.

Highlights

High prevalence of type 2 diabetes, which is developed from glucose disturbance and insulin resistance, has become a global health problem [1]
Several studies revealed that high maternal folic acid consumption increased the risk of allergy disease [11] and mammary tumours [12], and we found two studies on possible detrimental effect of maternal folic acid supplement (FolS) on glucose metabolism in offspring noteworthy: one is that in mouse models, gestational methyl donor supplement significantly increased body fat in offspring [13], this has not yet been proven in the general population; a recent population-based study observed that low maternal vitamin B12 accompanied with high folate concentration during pregnancy was associated with higher insulin resistance in offspring [14]
No differences in body weight gain and dietary intake were observed between each maternal group, while both recommended folic acid supplement (RFolS) and high folic acid supplement (HFolS) groups had significantly higher daily folic acid intakes than the control group (Table S1)

Summary

Introduction

High prevalence of type 2 diabetes, which is developed from glucose disturbance and insulin resistance, has become a global health problem [1]. As part of a classical western lifestyle, the high-fat diet (HFD) has been proven to be closely associated with glucose disturbance and insulin resistance. Habitual HFD generally induces dyslipidaemia, glucose disturbance, abnormal secretion of inflammatory factors, and further promotes insulin resistance and diabetes [2]. In addition to HFD, as suggested by accumulating evidence, unbalanced maternal nutrition contributes to the incidence and development of glucose disturbance and insulin resistance in offspring [3]. Intrauterine exposure to improper nutrition affects the expression of foetal genes, and programs the future risk of metabolic diseases in their later life [4], involving epigenetic changes such as aberrant DNA methylation as probable mechanisms. Because maternal folate supplement lowers risk of birth defects and Alzheimer’s disease, many countries encourage periconceptional folic acid (synthetic form of folate) supplement [6]

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Conclusion