Maternal folate deficiency and metabolic dysfunction in offspring

The importance of folate during pregnancy was established more than 80 years ago by Lucy Wills' ground-breaking studies of tropical macrocytic anaemia. More recently, it has become apparent that the adverse consequences of inadequate nutrient supply during early developmental may be exacerbated by over-nutrition postnatally. The present paper aims to review recent evidence that maternal methyl donor (notably folate) supply peri-conceptually and during pregnancy has long-term effects on offspring (metabolic) health. In addition, we propose the hypothesis that epigenetic mechanisms, especially DNA methylation, may mediate the effects of these early life nutritional insults. We discuss evidence from a natural experiment in human subjects which provides proof of principle for the hypothesis. We describe an attempt to test this hypothesis using a mouse model in which female C57Bl/6 mice were randomised to low or normal folate diets prior to, and during, pregnancy and lactation. Low maternal folate supply resulted in offspring that were more susceptible to detrimental metabolic effects of a high-fat diet fed from weaning, manifested as increased circulating TAG concentration. Interestingly, this metabolic phenotype in adult offspring occurred without any detectable change in adiposity, suggesting a different aetiological origin from the more commonly reported observation that maternal undernutrition leads to increased offspring adiposity and to symptoms of the Metabolic Syndrome. The widespread prevalence of overweight and obesity and of folate deficiency among women of child-bearing age highlights the possibility that this double nutritional insult may exacerbate the risk of metabolic disease in their offspring.