Search

Hormones have an important role in the regulation of fetal growth and development, especially in response to nutrient availability in utero. Using micro-CT and an electromagnetic three-point bend test, this study examined the effect of pancreas removal at 0.8 fraction of gestation on the developing bone structure and mechanical strength in fetal sheep. When fetuses were studied at 10 and 25 days after surgery, pancreatectomy caused hypoinsulinaemia, hyperglycaemia and growth retardation which was associated with low plasma concentrations of leptin and a marker of osteoclast activity and collagen degradation. In pancreatectomized fetuses compared to control fetuses, limb lengths were shorter, and trabecular (Tb) bone in the metatarsi showed greater bone volume fraction, Tb thickness, degree of anisotropy and porosity, and lower fractional bone surface area and Tb spacing. Mechanical strength testing showed that pancreas deficiency was associated with increased stiffness and a greater maximal weight load at fracture in a subset of fetuses studied near term. Overall, pancreas deficiency in utero slowed the growth of the fetal skeleton and adapted the developing bone to generate a more compact and connected structure. Maintenance of bone strength in growth-retarded limbs is especially important in a precocial species in preparation for skeletal loading and locomotion at birth.

The incidence of obesity is rising rapidly worldwide with the consequence that more women are entering pregnancy overweight or obese. This leads to an increased incidence of clinical complications during pregnancy and of poor obstetric outcomes. The offspring of obese pregnancies are often macrosomic at birth although there is also a subset of the progeny that are growth-restricted at term. Maternal obesity during pregnancy is also associated with cardiovascular, metabolic and endocrine dysfunction in the offspring later in life. As the interface between the mother and fetus, the placenta has a central role in programming intrauterine development and is known to adapt its phenotype in response to environmental conditions such as maternal undernutrition and hypoxia. However, less is known about placental function in the abnormal metabolic and endocrine environment associated with maternal obesity during pregnancy. This review discusses the placental consequences of maternal obesity induced either naturally or experimentally by increasing maternal nutritional intake and/or changing the dietary composition. It takes a comparative, multi-species approach and focusses on placental size, morphology, nutrient transport, metabolism and endocrine function during the later stages of obese pregnancy. It also examines the interventions that have been made during pregnancy in an attempt to alleviate the more adverse impacts of maternal obesity on placental phenotype. The review highlights the potential role of adaptations in placental phenotype as a contributory factor to the pregnancy complications and changes in fetal growth and development that are associated with maternal obesity.

Summary In all eutherian mammals, growth of the fetus is dependent upon a functional placenta, but whether and how the latter adapts to putative fetal signals is currently unknown. Here, we demonstrate, through fetal, endothelial, hematopoietic, and trophoblast-specific genetic manipulations in the mouse, that endothelial and fetus-derived IGF2 is required for the continuous expansion of the feto-placental microvasculature in late pregnancy. The angiocrine effects of IGF2 on placental microvasculature expansion are mediated, in part, through IGF2R and angiopoietin-Tie2/TEK signaling. Additionally, IGF2 exerts IGF2R-ERK1/2-dependent pro-proliferative and angiogenic effects on primary feto-placental endothelial cells ex vivo. Endothelial and fetus-derived IGF2 also plays an important role in trophoblast morphogenesis, acting through Gcm1 and Synb. Thus, our study reveals a direct role for the imprinted Igf2-Igf2r axis on matching placental development to fetal growth and establishes the principle that hormone-like signals from the fetus play important roles in controlling placental microvasculature and trophoblast morphogenesis., Graphical abstract, Highlights • Fetus-derived IGF2 controls placental microvasculature expansion in late gestation • The angiocrine effects of IGF2 are mediated via angiopoietins/Tek and IGF2R-ERK1/2 • Fetus-derived IGF2 also regulates trophoblast morphogenesis via Gcm1 and Synb • The imprinted Igf2-Igf2r axis matches placental development to fetal demand, The fetal signals that coordinate placental development to the nutritional needs of the growing fetus are currently unknown. Using genetic manipulations in the mouse, Sandovici et al. show that IGF2 produced by the fetus is a key signal that controls the expansion of the placental vascular tree in late pregnancy.

Hormones have an important role in regulating fetal metabolism in relation to the prevailing nutritional conditions both in late gestation and during the prepartum period as the fetus prepares for birth. In particular, the pancreatic, thyroid and adrenal hormones all affect fetal uptake and utilization of nutrients for oxidative metabolism, tissue accretion and fuel storage. These hormones also influence the fetal metabolic preparations for the nutritional transition from intra- to extra-uterine life. This review discusses the role of insulin, glucagon, thyroxine, tri-iodothyronine, cortisol and the catecholamines in these processes during normal intrauterine conditions and in response to maternal undernutrition with particular emphasis on the sheep fetus. It also considers the metabolic interactions between these hormones and their role in the maturation of key tissues, such as the liver, skeletal muscle and adipose tissue, in readiness for their new metabolic functions after birth. Endocrine regulation of fetal metabolism is shown to be multifactorial and dynamic with a central role in optimizing metabolic fitness for survival both in utero and at birth.

Glucocorticoids have an important role in development of the metabolic phenotype in utero. They act as environmental and maturational signals in adapting feto-placental metabolism to maximize the chances of survival both before and at birth. They influence placental nutrient handling and fetal metabolic processes to support fetal growth, fuel storage and energy production with respect to nutrient availability. More specifically, they regulate the transport, utilization and production of a range of nutrients by the feto-placental tissues that enables greater metabolic flexibility in utero while minimizing any further drain on maternal resources during periods of stress. Near term, the natural rise in fetal glucocorticoid concentrations also stimulates key metabolic adaptations that prepare tissues for the new energy demanding functions after birth. Glucocorticoids, therefore, have a central role in the metabolic communication between the mother, placenta and fetus that optimizes offspring metabolic phenotype for survival to reproductive age. This review discusses the effects of maternal and fetal glucocorticoids on the supply and utilization of nutrients by the feto-placental tissues with particular emphasis on studies using quantitative methods to assess metabolism in rodents and sheep in vivo during late pregnancy. It considers the routes of glucocorticoid overexposure in utero, including experimental administration of synthetic glucocorticoids, and the mechanisms by which these hormones control feto-placental metabolism at the molecular, cellular and systems levels. It also briefly examines the consequences of intrauterine glucocorticoid overexposure for postnatal metabolic health and the generational inheritance of metabolic phenotype.

In adults, glucocorticoids act to match the supply and demand for energy during physiological challenges, partly through actions on tissue mitochondrial oxidative phosphorylation (OXPHOS) capacity. However, little is known about the role of the natural prepartum rise in fetal glucocorticoid concentrations in preparing tissues for the increased postnatal energy demands. This study examined the effect of manipulating cortisol concentrations in fetal sheep during late gestation on mitochondrial OXPHOS capacity of two skeletal muscles with different postnatal locomotive functions. Mitochondrial content, biogenesis markers, respiratory rates and expression of proteins and genes involved in the electron transfer system (ETS) and OXPHOS efficiency were measured in the biceps femoris (BF) and superficial digital flexor (SDF) of fetuses either infused with cortisol before the prepartum rise or adrenalectomised to prevent this increment. Cortisol infusion increased mitochondrial content, biogenesis markers, substrate-specific respiration rates and abundance of ETS complex I and adenine nucleotide translocator (ANT1) in a muscle-specific manner that was more pronounced in the SDF than BF. Adrenalectomy reduced mitochondrial content and expression of PGC1α and ANT1 in both muscles, and ETS complex IV abundance in the SDF near term. Uncoupling protein gene expression was unaffected by cortisol manipulations in both muscles. Gene expression of the myosin heavy chain isoform, MHCIIx, was increased by cortisol infusion and reduced by adrenalectomy in the BF alone. These findings show that cortisol has a muscle-specific role in prepartum maturation of mitochondrial OXPHOS capacity with important implications for the health of neonates born pre-term or after intrauterine glucocorticoid overexposure.

Background: The fetal hypothalamic-pituitary-adrenal (HPA) axis plays a key role in the control of parturition and maturation of organ systems in preparation for birth. In hypothyroid fetuses, gestational length may be prolonged and maturational processes delayed. The extent to which the effects of thyroid hormone deficiency in utero on the timing of fetal maturation and parturition are mediated by changes to the structure and function of the fetal HPA axis is unknown. Methods: In twin sheep pregnancies where one fetus was thyroidectomized and the other sham-operated, this study investigated the effect of hypothyroidism on circulating concentrations of adrenocorticotrophic hormone (ACTH) and cortisol, and the structure and secretory capacity of the anterior pituitary and adrenal glands. The relative population of pituitary corticotrophs and the masses of the adrenal zones were assessed by immunohistochemical and stereological techniques. Adrenal mRNA abundances of key steroidogenic enzymes and growth factors were examined by quantitative polymerase chain reaction. Results: Hypothyroidism in utero reduced plasma concentrations of ACTH and cortisol. In thyroid-deficient fetuses, the mass of corticotrophs in the anterior pituitary gland was unexpectedly increased, while the mass of the zona fasciculata and its proportion of the adrenal gland were decreased. These structural changes were associated with lower adrenocortical mRNA abundances of insulin-like growth factor (IGF)-I and its receptor, and key steroidogenic enzymes responsible for glucocorticoid synthesis. The relative mass of the adrenal medulla and its proportion of the adrenal gland were increased by thyroid hormone deficiency in utero, without any change in expression of phenylethanolamine N-methyltransferase or the IGF system. Conclusions: Thyroid hormones are important regulators of the structure and secretory capacity of the pituitary-adrenal axis before birth. In hypothyroid fetuses, low plasma cortisol may be due to impaired adrenocortical growth and steroidogenic enzyme expression, secondary to low circulating ACTH concentration. Greater corticotroph population in the anterior pituitary gland of the hypothyroid fetus indicates compensatory cell proliferation and that there may be abnormal corticotroph capacity for ACTH synthesis and/or impaired hypothalamic input. Suppression of the development of the fetal HPA axis by thyroid hormone deficiency may contribute to the delay in fetal maturation and delivery observed in hypothyroid offspring.

Background: Development of adipose tissue before birth is essential for energy storage and thermoregulation in the neonate and for cardiometabolic health in later life. Thyroid hormones are important regulators of growth and maturation in fetal tissues. Offspring hypothyroid in utero are poorly adapted to regulate body temperature at birth and are at risk of becoming obese and insulin resistant in childhood. The mechanisms by which thyroid hormones regulate the growth and development of adipose tissue in the fetus, however, are unclear. Methods: This study examined the structure, transcriptome, and protein expression of perirenal adipose tissue (PAT) in a fetal sheep model of thyroid hormone deficiency during late gestation. Proportions of unilocular (UL) (white) and multilocular (ML) (brown) adipocytes, and UL adipocyte size, were assessed by histological and stereological techniques. Changes to the adipose transcriptome were investigated by RNA sequencing and bioinformatic analysis, and proteins of interest were quantified by Western blotting. Results: Hypothyroidism in utero resulted in elevated plasma insulin and leptin concentrations and overgrowth of PAT in the fetus, specifically due to hyperplasia and hypertrophy of UL adipocytes with no change in ML adipocyte mass. RNA sequencing and genomic analyses showed that thyroid deficiency affected 34% of the genes identified in fetal adipose tissue. Enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) pathways were associated with adipogenic, metabolic, and thermoregulatory processes, insulin resistance, and a range of endocrine and adipocytokine signaling pathways. Adipose protein levels of signaling molecules, including phosphorylated S6-kinase (pS6K), glucose transporter isoform 4 (GLUT4), and peroxisome proliferator-activated receptor γ (PPARγ), were increased by fetal hypothyroidism. Fetal thyroid deficiency decreased uncoupling protein 1 (UCP1) protein and mRNA content, and UCP1 thermogenic capacity without any change in ML adipocyte mass. Conclusions: Growth and development of adipose tissue before birth is sensitive to thyroid hormone status in utero. Changes to the adipose transcriptome and phenotype observed in the hypothyroid fetus may have consequences for neonatal survival and the risk of obesity and metabolic dysfunction in later life.

Mitochondria respond to a range of stimuli and function in energy production and redox homeostasis. However, little is known about the developmental and environmental control of mitochondria in the placenta, an organ vital for fetal growth and pregnancy maintenance in eutherian mammals. Using respirometry and molecular analyses, the present study examined mitochondrial function in the distinct transport and endocrine zones of the mouse placenta during normal pregnancy and maternal inhalation hypoxia. The data show that mitochondria of the two zones adopt different strategies in modulating their respiration, substrate use, biogenesis, density, and efficiency to best support the growth and energy demands of fetoplacental tissues during late gestation in both normal and hypoxic conditions. The findings have important implications for environmentally induced adaptations in mitochondrial function in other tissues and for compromised human pregnancy in which hypoxia and alterations in placental mitochondrial function are associated with poor outcomes like fetal growth restriction.

Pregnancy success and life-long health depend on a cooperative interaction between the mother and the fetus in the allocation of resources. As the site of materno-fetal nutrient transfer, the placenta is central to this interplay; however, the relative importance of the maternal versus fetal genotypes in modifying the allocation of resources to the fetus is unknown. Using genetic inactivation of the growth and metabolism regulator, Pik3ca (encoding PIK3CA also known as p110α, α/+), we examined the interplay between the maternal genome and the fetal genome on placental phenotype in litters of mixed genotype generated through reciprocal crosses of WT and α/+ mice. We demonstrate that placental growth and structure were impaired and associated with reduced growth of α/+ fetuses. Despite its defective development, the α/+ placenta adapted functionally to increase the supply of maternal glucose and amino acid to the fetus. The specific nature of these changes, however, depended on whether the mother was α/+ or WT and related to alterations in endocrine and metabolic profile induced by maternal p110α deficiency. Our findings thus show that the maternal genotype and environment programs placental growth and function and identify the placenta as critical in integrating both intrinsic and extrinsic signals governing materno-fetal resource allocation.

Widespread expression of leptin and its receptor in developing cartilage and bone suggests that leptin may regulate bone growth and development in the fetus. Using microcomputed tomography, this study investigated the effects of exogenous leptin and leptin receptor antagonism on aspects of bone structure in the sheep fetus during late gestation. From 125 to 130 days of gestation (term ~145 days), chronically catheterized singleton sheep fetuses were infused intravenously for 5 days with either saline (0.9% saline, n = 13), recombinant ovine leptin at two doses (0.6 mg·kg-1·day-1 LEP1, n = 10 or 1.4 mg·kg-1·day-1 LEP2, n = 7), or recombinant superactive ovine leptin receptor antagonist (4.6 mg·kg-1·day-1 SOLA, n = 6). No significant differences in plasma insulin-like growth factor-I, osteocalcin, calcium, inorganic phosphate, or alkaline phosphatase were observed between treatment groups. Total femur midshaft diameter and metatarsal lumen diameter were narrower in male fetuses treated with exogenous leptin. In a fixed length of femur midshaft, total and bone volumes were reduced by the higher dose of leptin; nonbone space volume was lower in both groups of leptin-treated fetuses. Leptin infusion caused increments in femur porosity and connectivity density, and vertebral trabecular thickness. Leptin receptor antagonism decreased trabecular spacing and increased trabecular number, degree of anisotrophy, and connectivity density in the lumbar vertebrae. The increase in vertebral porosity observed following leptin receptor antagonism was greater in the malecompared with female, fetuses. Therefore, leptin may have a role in the growth and development of the fetal skeleton, dependent on the concentration of leptin, sex of the fetus, and bone type examined.

Antenatal synthetic glucocorticoids promote fetal maturation in pregnant women at risk of preterm delivery and their mechanism of action may involve other endocrine systems. This study investigated the effect of maternal dexamethasone treatment, at clinically relevant doses, on components of the renin-angiotensin system (RAS) in the pregnant ewe and fetus. From 125 days of gestation (term, 145 ± 2 d), 10 ewes carrying single fetuses of mixed sex (3 female, 7 male) were injected twice im, at 10-11 pm, with dexamethasone (2 × 12 mg, n = 5) or saline (n = 5) at 24-hour intervals. At 10 hours after the second injection, maternal dexamethasone treatment increased angiotensin-converting enzyme (ACE) mRNA levels in the fetal lungs, kidneys, and heart and ACE concentration in the circulation and lungs, but not kidneys, of the fetuses. Fetal cardiac mRNA abundance of angiotensin II (AII) type 2 receptor decreased after maternal dexamethasone treatment. Between the two groups of fetuses, there were no significant differences in plasma angiotensinogen or renin concentrations; in transcript levels of renal renin, or AII type 1 or 2 receptors in the lungs and kidneys; or in pulmonary, renal or cardiac protein content of the AII receptors. In the pregnant ewes, dexamethasone administration increased pulmonary ACE and plasma angiotensinogen, and decreased plasma renin, concentrations. Some of the effects of dexamethasone treatment on the maternal and fetal RAS were associated with altered insulin and thyroid hormone activity. Changes in the local and circulating RAS induced by dexamethasone exposure in utero may contribute to the maturational and tissue-specific actions of antenatal glucocorticoid treatment.

The placenta is the main determinant of fetal growth and development in utero. It supplies all the nutrients and oxygen required for fetal growth and secretes hormones that facilitate maternal allocation of nutrients to the fetus. Furthermore, the placenta responds to nutritional and metabolic signals in the mother by altering its structural and functional phenotype which can lead to changes in maternal resource allocation to the fetus. The molecular mechanisms by which the placenta senses and responds to environmental cues are poorly understood. This review discusses the role of the insulin-like growth factors (IGFs) in controlling placental resource allocation to fetal growth, particularly in response to adverse gestational environments. In particular, it assesses the impact of the IGFs and their signalling machinery on placental morphogenesis, substrate transport and hormone secretion, primarily in the laboratory species, although it draws on data from human and other species where relevant. It also considers the role of the IGFs as environmental signals in linking resource availability, to fetal growth through changes in the morphological and functional phenotype of the placenta. As altered fetal growth is associated with increased perinatal morbidity and mortality and a greater risk of developing adult-onset diseases in later life, understanding the role of IGFs during pregnancy in regulating placental resource allocation to fetal growth is important for identifying the mechanisms underlying the developmental programming of offspring phenotype by suboptimal intrauterine growth.

Stress during pregnancy is associated with metabolic dysfunction in the adult offspring in human and other animals. However, little is known about the metabolic effects of pregnancy stress on the mothers and fetuses during pregnancy itself. This study aimed to determine the consequences of the common experimental procedures of injection and single housing in pregnant rats on fetal and maternal hepatic glucogenic capacities. On day (D) 20 of pregnancy, feto‐placental weights and the glycogen content and activities of phosphoenolpyruvate carboxykinase (PEPCK) and glucose‐6‐phosphatase (G6Pase) of fetal and maternal liver were measured in rats pair or single housed from D1 with or without saline injection from D15 to D19. Housing and saline injection both affected hepatic glucogenic capacity. In maternal liver, saline injection but not housing reduced glycogen content and raised G6Pase activity, whereas housing but not treatment increased PEPCK activity. In fetuses, housing and injection interacted in regulating PEPCK activity and reducing hepatic glycogen content and placental weight. Body weight was decreased and hepatic G6Pase increased by injection but not housing in the fetuses. Single‐housed dams ate less than those pair‐housed near term while saline injection elevated maternal plasma corticosterone concentrations. Thus, single housing and saline injection are both stresses during rat pregnancy that alter feto‐placental weight and hepatic glucogenic capacity of the fetuses and dams near term. Routine experimental procedures per se may, therefore, have consequences for offspring hepatic phenotype as well as modifying the outcomes of dietary and other environmental challenges during pregnancy.

Key points In the Western world, obesogenic diets containing high fat and high sugar (HFHS) are commonly consumed during pregnancy, although their effects on the metabolism of the mother, in relation to feto‐placental glucose utilization and growth, are unknown.In the present study, the consumption of an obesogenic HFHS diet compromised maternal glucose tolerance and insulin sensitivity in late pregnancy in association with dysregulated lipid and glucose handling by the dam.These maternal metabolic changes induced by HFHS feeding were related to altered feto‐placental glucose metabolism and growth.A HFHS diet during pregnancy therefore causes maternal metabolic dysfunction with consequences for maternal nutrient allocation for fetal growth.These findings have implications for the health of women and their infants, who consume obesogenic diets during pregnancy. Abstract In the Western world, obesogenic diets containing high fat and high sugar (HFHS) are commonly consumed during pregnancy. However, the impacts of a HFHS diet during pregnancy on maternal insulin sensitivity and signalling in relation to feto‐placental growth and glucose utilization are unknown. The present study examined the effects of a HFHS diet during mouse pregnancy on maternal glucose tolerance and insulin resistance, as well as, on feto‐placental glucose metabolism. Female mice were fed a control or HFHS diet from day (D) 1 of pregnancy (term = D20.5). At D16 or D19, dams were assessed for body composition, metabolite and hormone concentrations, tissue abundance of growth and metabolic signalling pathways, glucose tolerance and utilization and insulin sensitivity. HFHS feeding perturbed maternal insulin sensitivity in late pregnancy; hepatic insulin sensitivity was higher, whereas sensitivity of the skeletal muscle and white adipose tissue was lower in HFHS than control dams. These changes were accompanied by increased adiposity and reduced glucose production and glucose tolerance of HFHS dams. The HFHS diet also disturbed the hormone and metabolite milieu and altered expression of growth and metabolic signalling pathways in maternal tissues. Furthermore, HFHS feeding was associated with impaired feto‐placental glucose metabolism and growth. A HFHS diet during pregnancy therefore causes maternal metabolic dysfunction with consequences for maternal nutrient allocation for fetal growth. These findings have implications for the health of women and their infants, who consume HFHS diets during pregnancy., Key points In the Western world, obesogenic diets containing high fat and high sugar (HFHS) are commonly consumed during pregnancy, although their effects on the metabolism of the mother, in relation to feto‐placental glucose utilization and growth, are unknown.In the present study, the consumption of an obesogenic HFHS diet compromised maternal glucose tolerance and insulin sensitivity in late pregnancy in association with dysregulated lipid and glucose handling by the dam.These maternal metabolic changes induced by HFHS feeding were related to altered feto‐placental glucose metabolism and growth.A HFHS diet during pregnancy therefore causes maternal metabolic dysfunction with consequences for maternal nutrient allocation for fetal growth.These findings have implications for the health of women and their infants, who consume obesogenic diets during pregnancy.

Glucocorticoids (GCs) are important environmental and maturational signals during intrauterine development. Toward term, the maturational rise in fetal glucocorticoid receptor concentrations decreases fetal growth and induces differentiation of key tissues essential for neonatal survival. When cortisol levels rise earlier in gestation as a result of suboptimal conditions for fetal growth, the switch from tissue accretion to differentiation is initiated prematurely, which alters the phenotype that develops from the genotype inherited at conception. Although this improves the chances of survival should delivery occur, it also has functional consequences for the offspring long after birth. Glucocorticoids are, therefore, also programming signals that permanently alter tissue structure and function during intrauterine development to optimize offspring fitness. However, if the postnatal environmental conditions differ from those signaled in utero, the phenotypical outcome of early-life glucocorticoid receptor overexposure may become maladaptive and lead to physiological dysfunction in the adult. This review focuses on the role of GCs in developmental programming, primarily in farm species. It examines the factors influencing GC bioavailability in utero and the effects that GCs have on the development of fetal tissues and organ systems, both at term and earlier in gestation. It also discusses the windows of susceptibility to GC overexposure in early life together with the molecular mechanisms and long-term consequences of GC programming with particular emphasis on the cardiovascular, metabolic, and endocrine phenotype of the offspring.

In human and ovine fetuses, glucocorticoids stimulate leptin secretion, although the extent to which leptin mediates the maturational effects of glucocorticoids on pulmonary development is unclear. This study investigated the effects of leptin administration on indices of lung structure and function before birth. Chronically catheterized singleton sheep fetuses were infused iv for 5 days with either saline or recombinant ovine leptin (0.5 mg/kg · d leptin (LEP), 0.5 LEP or 1.0 mg/kg · d, 1.0 LEP) from 125 days of gestation (term ∼145 d). Over the infusion, leptin administration increased plasma leptin, but not cortisol, concentrations. On the fifth day of infusion, 0.5 LEP reduced alveolar wall thickness and increased the volume at closing pressure of the pressure-volume deflation curve, interalveolar septal elastin content, secondary septal crest density, and the mRNA abundance of the leptin receptor (Ob-R) and surfactant protein (SP) B. Neither treatment influenced static lung compliance, maximal lung volume at 40 cmH2O, lung compartment volumes, alveolar surface area, pulmonary glycogen, protein content of the long form signaling Ob-Rb or phosphorylated signal transducers and activators of transcription-3, or mRNA levels of SP-A, C, or D, elastin, vascular endothelial growth factor-A, the vascular endothelial growth factor receptor 2, angiotensin-converting enzyme, peroxisome proliferator-activated receptor γ, or parathyroid hormone-related peptide. Leptin administration in the ovine fetus during late gestation promotes aspects of lung maturation, including up-regulation of SP-B.

Key points Hypoxia is a major cause of fetal growth restriction, particularly at high altitude, although little is known about its effects on placental phenotype and resource allocation to fetal growth.In the present study, maternal hypoxia induced morphological and functional changes in the mouse placenta, which depended on the timing and severity of hypoxia, as well as the degree of maternal hypophagia.Hypoxia at 13% inspired oxygen induced beneficial changes in placental morphology, nutrient transport and metabolic signalling pathways associated with little or no change in fetal growth, irrespective of gestational age.Hypoxia at 10% inspired oxygen adversely affected placental phenotype and resulted in severe fetal growth restriction, which was due partly to maternal hypophagia.There is a threshold between 13% and 10% inspired oxygen, corresponding to altitudes of ∼3700 m and 5800 m, respectively, at which the mouse placenta no longer adapts to support fetal resource allocation. This has implications for high altitude human pregnancies. Abstract The placenta adapts its transport capacity to nutritional cues developmentally, although relatively little is known about placental transport phenotype in response to hypoxia, a major cause of fetal growth restriction. The present study determined the effects of both moderate hypoxia (13% inspired O2) between days (D)11 and D16 or D14 and D19 of pregnancy and severe hypoxia (10% inspired O2) from D14 to D19 on placental morphology, transport capacity and fetal growth on D16 and D19 (term∼D20.5), relative to normoxic mice in 21% O2. Placental morphology adapted beneficially to 13% O2; fetal capillary volume increased at both ages, exchange area increased at D16 and exchange barrier thickness reduced at D19. Exposure to 13% O2 had no effect on placental nutrient transport on D16 but increased placental uptake and clearance of 3H‐methyl‐d‐glucose at D19. By contrast, 10% O2 impaired fetal vascularity, increased barrier thickness and reduced placental 14C‐methylaminoisobutyric acid clearance at D19. Consequently, fetal growth was only marginally affected in 13% O2 (unchanged at D16 and −5% at D19) but was severely restricted in 10% O2 (−21% at D19). The hypoxia‐induced changes in placental phenotype were accompanied by altered placental insulin‐like growth factor (IGF)‐2 expression and insulin/IGF signalling, as well as by maternal hypophagia depending on the timing and severity of the hypoxia. Overall, the present study shows that the mouse placenta can integrate signals of oxygen and nutrient availability, possibly through the insulin‐IGF pathway, to adapt its phenotype and optimize maternal resource allocation to fetal growth during late pregnancy. It also suggests that there is a threshold between 13% and 10% inspired O2 at which these adaptations no longer occur., Key points Hypoxia is a major cause of fetal growth restriction, particularly at high altitude, although little is known about its effects on placental phenotype and resource allocation to fetal growth.In the present study, maternal hypoxia induced morphological and functional changes in the mouse placenta, which depended on the timing and severity of hypoxia, as well as the degree of maternal hypophagia.Hypoxia at 13% inspired oxygen induced beneficial changes in placental morphology, nutrient transport and metabolic signalling pathways associated with little or no change in fetal growth, irrespective of gestational age.Hypoxia at 10% inspired oxygen adversely affected placental phenotype and resulted in severe fetal growth restriction, which was due partly to maternal hypophagia.There is a threshold between 13% and 10% inspired oxygen, corresponding to altitudes of ∼3700 m and 5800 m, respectively, at which the mouse placenta no longer adapts to support fetal resource allocation. This has implications for high altitude human pregnancies.

The effects of endogenous and synthetic glucocorticoids on fetal lung maturation are well-established, although the role of leptin in lung development before birth is unclear. This study examined mRNA and protein levels of the signalling long-form leptin receptor (Ob-Rb) in fetal ovine lungs towards term, and after experimental manipulation of glucocorticoid levels in utero by fetal cortisol infusion or maternal dexamethasone treatment. In fetal ovine lungs, Ob-Rb protein was localised to bronchiolar epithelium, bronchial cartilage, vascular endothelium, alveolar macrophages and type II pneumocytes. Pulmonary Ob-Rb mRNA abundance increased between 100 (0.69 fractional gestational age) and 144 days (0.99) of gestation, and by 2-4-fold in response to fetal cortisol infusion and maternal dexamethasone treatment. In contrast, pulmonary Ob-Rb protein levels decreased near term and were halved by glucocorticoid treatment, without any significant change in phosphorylated signal transducer and activator of transcription-3 (pSTAT3) at Ser727, total STAT3 or the pulmonary pSTAT3:STAT3 ratio. Leptin mRNA was undetectable in fetal ovine lungs at the gestational ages studied. These findings demonstrate differential control of pulmonary Ob-Rb transcript abundance and protein translation, and/or post-translational processing, by glucocorticoids in utero. Localisation of Ob-Rb in the fetal ovine lungs, including alveolar type II pneumocytes, suggests a role for leptin signalling in the control of lung growth and maturation before birth.

Before birth, glucocorticoids retard growth, although the extent to which this is mediated by changes in insulin signalling pathways in the skeletal muscle of the fetus is unknown. The current study determined the effects of endogenous and synthetic glucocorticoid exposure on insulin signalling proteins in skeletal muscle of fetal sheep during late gestation. Experimental manipulation of fetal plasma glucocorticoid concentration was achieved by fetal cortisol infusion and maternal dexamethasone treatment. Cortisol infusion significantly increased muscle protein levels of Akt2 and phosphorylated Akt at Ser473, and decreased protein levels of phosphorylated forms of mTOR at Ser2448 and S6K at Thr389. Muscle GLUT4 protein expression was significantly higher in fetuses whose mothers were treated with dexamethasone compared to those treated with saline. There were no significant effects of glucocorticoid exposure on muscle protein abundance of IR-β, IGF-1R, PKCζ, Akt1, calpastatin or muscle glycogen content. The present study demonstrated that components of the insulin signalling pathway in skeletal muscle of the ovine fetus are influenced differentially by naturally occurring and synthetic glucocorticoids. These findings may provide a mechanism by which elevated concentrations of endogenous glucocorticoids retard fetal growth.

The placenta is arguably the most important organ of the body, but paradoxically the most poorly understood. During its transient existence, it performs actions that are later taken on by diverse separate organs, including the lungs, liver, gut, kidneys and endocrine glands. Its principal function is to supply the fetus, and in particular, the fetal brain, with oxygen and nutrients. The placenta is structurally adapted to achieve this, possessing a large surface area for exchange and a thin interhaemal membrane separating the maternal and fetal circulations. In addition, it adopts other strategies that are key to facilitating transfer, including remodelling of the maternal uterine arteries that supply the placenta to ensure optimal perfusion. Furthermore, placental hormones have profound effects on maternal metabolism, initially building up her energy reserves and then releasing these to support fetal growth in later pregnancy and lactation post-natally. Bipedalism has posed unique haemodynamic challenges to the placental circulation, as pressure applied to the vena cava by the pregnant uterus may compromise venous return to the heart. These challenges, along with the immune interactions involved in maternal arterial remodelling, may explain complications of pregnancy that are almost unique to the human, including pre-eclampsia. Such complications may represent a trade-off against the provision for a large fetal brain.

Dexamethasone treatment of F0 pregnant rodents alters F1 placental function and adult cardiometabolic phenotype. The adult phenotype is transmitted to the F2 generation without further intervention, but whether F2 placental function is altered by F0 dexamethasone treatment remains unknown. In the present study, F0 mice were untreated or received dexamethasone (0.2 µg g–1 day–1, s.c.) over Days 11–15 or 14–18 of pregnancy (term Day 21). Depending on the period of F0 dexamethasone treatment, F1 offspring were lighter at birth or grew more slowly until weaning (P