Regulation of maternal-fetal metabolic communication

Abstract

Pregnancy may be the most nutritionally sensitive stage in the life cycle, and improved metabolic health during gestation and early postnatal life can reduce the risk of chronic disease in adulthood. Successful pregnancy requires coordinated metabolic, hormonal, and immunological communication. In this review, maternal-fetal metabolic communication is defined as the bidirectional communication of nutritional status and metabolic demand by various modes including circulating metabolites, endocrine molecules, and other secreted factors. Emphasis is placed on metabolites as a means of maternal-fetal communication by synthesizing findings from studies in humans, non-human primates, domestic animals, rabbits, and rodents. In this review, fetal, placental, and maternal metabolic adaptations are discussed in turn. (1) Fetal macronutrient needs are summarized in terms of the physiological adaptations in place to ensure their proper allocation. (2) Placental metabolite transport and maternal physiological adaptations during gestation, including changes in energy budget, are also discussed. (3) Maternal nutrient limitation and metabolic disorders of pregnancy serve as case studies of the dynamic nature of maternal-fetal metabolic communication. The review concludes with a summary of recent research efforts to identify metabolites, endocrine molecules, and other secreted factors that mediate this communication, with particular emphasis on serum/plasma metabolomics in humans, non-human primates, and rodents. A better understanding of maternal-fetal metabolic communication in health and disease may reveal novel biomarkers and therapeutic targets for metabolic disorders of pregnancy.

Keywords: Biomarkers; Fetal metabolism; Maternal–fetal; Metabolomics; Placenta; Pregnancy.

Fig. 1

Maternal–fetal metabolic communication relies on maternal, placental, and fetal adaptations. Maternal–fetal metabolic communication is the bidirectional communication of nutritional status and metabolic demand. Circulating metabolites, endocrine molecules, circulating cells, and secreted factors such as exosomes and extracellular vesicles can all contribute to this communication. Maternal metabolic adaptations include increased metabolic flexibility and building up maternal energy stores while providing nutrients to support placental/fetal growth and metabolism. Fetal metabolism is characterized by high anabolic demand, and changes in fetal metabolism during late gestation may prepare, or program, the offspring for early postnatal life

Fig. 2

Maternal metabolic adaptations. Physiological adaptations during pregnancy ensure adequate nutrient delivery to the developing fetus. Adaptations affect whole-body metabolism of glucose, lipids, and amino acids. Polytocous species have the additional challenges of higher fetal demand relative to maternal energy budget and differences in uterine blood flow based on fetal position in the uterine horn. UA uterine artery

Fig. 3

Enzymic differentiation is the process by which fetal, neonatal, and adolescent tissues develop the enzymatic functions of adult tissues [93]. Shown here is a schematic representation of the transition from fetal to early postnatal metabolism. Mitochondrial content, represented in red, increases in brain, heart, and liver over this period of development. As an example, the capacity for gluconeogenesis is represented in blue and increases during late fetal development with a robust increase after birth (due to postnatal metabolic and hormonal signals). In utero nutritional stress, communicated via maternal circulating factors, may cause the fetal portion of the curve to be activated prematurely and shifted left, as shown by the dashed blue line. Both fetal under- and overnutrition have been posited to prime fetal liver metabolism for the postnatal transition [48, 98]. A similar trend could be shown for other metabolic processes that increase postnatally, such as fatty acid oxidation in the heart

Fig. 4

Placental metabolism affects maternal–fetal metabolic communication. The placenta is not a passive conduit for nutrient and waste transfer. Placental metabolism can sequester nutrients from the mother, store nutrients for subsequent delivery to the fetus, or provide new or bio-transformed substrates for fetal nutrition. Examples are provided of lipids metabolized by the placenta in these ways. Fas fatty acids

Fig. 5

The accelerated fasting response during pregnancy. a Fasting in normal late term pregnancy leads to robust increases in circulating lipids and exaggerated ketone body production [161], shown here as representative plasma concentrations in response to fasting during late gestation in red (black dashed line is non-pregnant control). Additional features of the accelerated fasting (or accelerated starvation) response include increased fat mobilization from adipose, decreased blood glucose despite enhanced gluconeogenic potential, and increased maternal muscle catabolism. Increased maternal utilization of lipids spares glucose and amino acids for fetal uptake. b Late gestation is also characterized by “facilitated anabolism” which describes aggregate changes in maternal circulating factors that promote fetal growth. Accelerated fasting and facilitated anabolism result in a pattern of dynamic metabolic oscillations in maternal fuel utilization between fed and fasted states in late gestation [5]. NEFAs non-esterified fatty acids