Placental metabolic reprogramming: do changes in the mix of energy-generating substrates modulate fetal growth?

Abstract

Insufficient oxygen leads to the cessation of growth in favor of cellular survival. Our unique model of high-altitude human pregnancy indicates that hypoxia-induced reductions in fetal growth occur at higher levels of oxygen than previously described. Fetal PO2 is surprisingly high and fetal oxygen consumption unaffected by high altitude, whereas fetal glucose delivery and consumption decrease. Placental delivery of energy-generating substrates to the fetus is thus altered by mild hypoxia, resulting in maintained fetal oxygenation but a relative fetal hypoglycemia. Our data point to this altered mix of substrates as a potential initiating factor in reduced fetal growth, since oxygen delivery is adequate. These data support the existence, in the placenta, of metabolic reprogramming mechanisms, previously documented in tumor cells, whereby HIF-1 stimulates reductions in mitochondrial oxygen consumption at the cost of increased glucose consumption. Decreased oxygen consumption is not due to substrate (oxygen) limitation but rather results from active inhibition of mitochondrial oxygen utilization. We suggest that under hypoxic conditions, metabolic reprogramming in the placenta decreases mitochondrial oxygen consumption and increases anerobic glucose consumption, altering the mix of energy-generating substrates available for transfer to the fetus. Increased oxygen is available to support the fetus, but at the cost of less glucose availability, leading to a hypoglycemia-mediated decrease in fetal growth. Our data suggest that metabolic reprogramming may be an initiating step in the progression to more severe forms of fetal growth restriction and points to the placenta as the pivotal source of fetal programming in response to an adverse intrauterine environment.

Activation of the nuclear receptor PPARα regulates lipid metabolism in foetal liver from diabetic rats: implications in diabetes‐induced foetal overgrowth

“…In the rat, glycaemia values are low at the foetal stage and increases before parturition [39]. The maternal-to-foetal glucose gradient varies significantly among species, being sharper in sheep and rats than in mice and humans [39][40][41][42][43]. Increased metabolic substrates in foetal circulation and increased foetal overgrowth have been previously addressed in human diabetic gestations and in different diabetes and pregnancy experimental models [3,4,10,44,45].…”

Placenta: The Forgotten Organ

“…During isolated hypoxia induced at high altitude, for example, the human placenta decreases its consumption of oxygen and increases glycolysis to maintain its bioenergetic needs (Postigo et al 2009), and placental growth is not compromised. This results in the preservation of fetal O 2 delivery at the expense of glucose (Illsley et al 2010). Given that fetal hypoglycemia is strongly associated with fetal growth restriction, this results in impaired fetal growth.…”

Placental origins of adverse pregnancy outcomes: potential molecular targets: an Executive Workshop Summary of the Eunice Kennedy Shriver National Institute of Child Health and Human Development

“…Maternal partial pressure of O 2 in arterial blood (P a O 2 ) falls considerably at ≥2700 meters (m) elevation, and due to the sigmoid shape of the O 2 dissociation curve, P a O 2 falls precipitously at >3000 m. Even in pregnancies with entirely normal outcomes, physiologically lowered maternal P a O 2 results in a progressive slowing of the 3 rd -trimester fetal growth trajectory 220,221 This is despite significant placental adaptation both structurally (increased angiogenesis, decreased vascular syncytial membrane thickness) and metabolically. 222,223,224,225,226,227 Altitude studies in vivo showed that the human placenta subjected to hypoxic stress engages in a highly conserved process most obviously seen in solid tumors. 228,229,230,231 Metabolic reprogramming is a reversible form of hypometabolism in which an effective, largely mitochondrial driven switch from oxidative phosphorylation to aerobic (i.e.…”