Maternal obesity disrupts the methionine cycle in baboon pregnancy.

Peter W Nathanielsz,Ralph Green,Thomas J Mcdonald,Guoyao Wu,Marie A Caudill,Jian Yan,Mark Nijland,Joshua W Miller

doi:10.14814/phy2.12564

Abstract

Maternal intake of dietary methyl-micronutrients (e.g. folate, choline, betaine and vitamin B-12) during pregnancy is essential for normal maternal and fetal methionine metabolism, and is critical for important metabolic processes including those involved in developmental programming. Maternal obesity and nutrient excess during pregnancy influence developmental programming potentially predisposing adult offspring to a variety of chronic health problems. In the present study, we hypothesized that maternal obesity would dysregulate the maternal and fetal methionine cycle. To test this hypothesis, we developed a nulliparous baboon obesity model fed a high fat, high energy diet (HF-HED) prior to and during gestation, and examined methionine cycle biomarkers (e.g., circulating concentrations of homocysteine, methionine, choline, betaine, key amino acids, folate, and vitamin B-12). Animals were group housed allowing full physical activity and social interaction. Maternal prepregnancy percent body fat was 5% in controls and 19% in HF-HED mothers, while fetal weight was 16% lower in offspring of HF-HED mothers at term. Maternal and fetal homocysteine were higher, while maternal and fetal vitamin B-12 and betaine were lower in the HF-HED group. Elevations in circulating maternal folate were evident in the HF-HED group indicating impaired folate metabolism (methyl-trap) as a consequence of maternal vitamin B-12 depletion. Finally, fetal methionine, glycine, serine, and taurine were lower in the HF-HED fetuses. These data show that maternal obesity disturbs the methionine cycle in primate pregnancy, providing a mechanism for the epigenetic changes observed among obese pregnant women and suggesting diagnostic and therapeutic opportunities in human pregnancies complicated by obesity.

Highlights

Nutritional imbalance and obesity during pregnancy predispose adult offspring to a variety of chronic health problems through a process known as developmental programming (Barker 1999; Armitage et al 2004; Fernandez-Twinn and Ozanne 2010; Alfaradhi and Ozanne 2011; Sullivan et al 2011; Shasa et al 2015)
Within the one-carbon metabolic network, the methionine cycle (Fig. 1) provides methyl groups from methionine and other dietary methyl-micronutrients to several important metabolic processes (Kalhan and Marczewski 2012) including those involved in developmental programming
While there are studies showing disturbances in the methionine cycle and gene specific DNA methylation as a result of maternal nutritional imbalances in rodent pregnancy (Lillycrop et al 2010), few studies have been conducted in pregnant nonhuman primates (Blocker et al 1989; Burbacher et al 2004; McCurdy 2009)

Summary

Introduction

Nutritional imbalance and obesity during pregnancy predispose adult offspring to a variety of chronic health problems through a process known as developmental (or fetal) programming (Barker 1999; Armitage et al 2004; Fernandez-Twinn and Ozanne 2010; Alfaradhi and Ozanne 2011; Sullivan et al 2011; Shasa et al 2015). Reduction of folic acid to tetrahydrofolate (THF; the active form of folate) by dihydrofolate reductase in the human liver occurs at less than 2% the rate observed in rat liver (Bailey and Ayling 2009). This lower rate of reduction in humans may result in the accumulation of dihydrofolate, which can compete with THF as a substrate for polyglutamyl synthase, resulting in diminished levels of the active folate polyglutamate cofactors required for one-carbon metabolism

Methods

Results

Conclusion