Review: Placental transport and metabolism of energy substrates in maternal obesity and diabetes
Introduction
The global prevalence of overweight, obesity, and diabetes mellitus is increasing [1]. In developed nations, one third of pregnant women are overweight or obese [2] and 5–10% have diabetes in pregnancy [3]. In these complicated pregnancies, physiological changes are exaggerated, including alterations to lipoprotein levels and enhanced gluconeogenesis [4]. High maternal weight, dyslipidemia, and/or hyperglycemia place mother and child at risk, with the most common adverse outcome being high birth weight (macrosomia) [5], [6], [7], [8], [9], [10], [11], [12]. Large for gestational age infants born to women with GDM have a higher percent body fat when compared to infants from uncomplicated pregnancies [13] and ∼70% of mothers [14] and offspring [15] will develop type 2 diabetes in later life.
The influence of maternal disease on fetal outcomes is governed, to a large extent, by the placenta. In maternal obesity and hyperglycemia, placental size is greater and structural changes including thrombosis may be evident [16], [17], [18], [19]. There are three main mechanisms that regulate fetal exposure to maternal nutrients: direct placental transfer, placental consumption, and placental conversion into alternative sources of fuel [20], [21]. While direct transfer is often regarded as the predominant pathway in regulating maternal-fetal exchange, the placenta has a high metabolic activity, which is affected by an obesogenic and/or diabetogenic environment. Alterations in placental metabolism may serve as a checkpoint to regulate fetal exposure and, ultimately, determine the degree of influence that abnormal maternal metabolism has on fetal growth and development (Fig. 1) [22].
Section snippets
Glucose transport and metabolism
Glucose is the predominant source of energy for the fetus and placenta [23]. There is limited capacity for the fetus to generate its own glucose and almost all of fetal glucose is derived from the mother [24], [25]. Net glucose transfer is determined by placental transporter density, the maternal-fetal concentration gradient, and placental glucose metabolism [26].
Glucose transfer across the placenta occurs via the family of facilitated glucose transporters (GLUTs). In the human
Lipid transport and metabolism
Fetal growth and development is also supported by free fatty acids and the constituent fatty acids and cholesterol that are transported in maternal lipoproteins. Markers of fetal cholesterol synthesis are very low in early pregnancy and increase only after 19 weeks gestation [50]. Placental transfer of lipoproteins is facilitated by lipoprotein receptors, lipases (lipoprotein lipase (LPL), endothelial lipase (EL), hormone sensitive lipase (HSL) and adipose triglyceride lipase (ATGL)), and fatty
Amino acid transport and metabolism
Amino acids are important substrates for the formation of proteins and nucleic acids in the fetus and placental transport is a tightly regulated process. Maternal amino acids are transported against the concentration gradient with placental intervillous concentrations generally exceeding maternal concentrations by two-fold [85], [86]. The concentrations in the umbilical vein mirror those of the placental intervillous space for most amino acids [85]. The high amino acid concentrations in the
Conclusions
In pregnancies complicated by obesity and/or diabetes, glucose appears to be the preferred energy substrate for placental metabolism - its uptake increasing in both states. Glucose transport and metabolism, however, are not merely modulated by maternal glucose per se, but likely to involve a complex and dynamic interplay with other energy substrates and fetal growth factors. Lipid processing and transfer by the placenta is influenced by maternal BMI, glucose status, and inflammation. Amino acid
Conflict of interest
None.
Acknowledgments
LAG was supported by a fellowship from the National Health and Medical Research Council (NHMRC) (APP1089763) and Heart Foundation (Australia) (100519). HLB is supported by an Australian Diabetes Society – Skip Martin Early Career Research Fellowship. This review was generated as part of the Queensland Perinatal Consortium Inaugural Conference held on July 15th, 2016 in Brisbane, Queensland Australia. The conference was supported by an Intra-Faculty Collaborative Workshop grant from the Faculty
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