Biomedical subjects

I C McMillen

Publications and source records attributed to I C McMillen.

At least 19 recordsLinked to original sources

PubMed2007

Maternal nutrient restriction in early pregnancy programs hepatic mRNA expression of growth-related genes and liver size in adult male sheep.

The liver is a major metabolic and endocrine organ of critical importance in the regulation of growth and metabolism. Its function is determined by a complex interaction of nutritionally regulated counter-regulatory hormones. The extent to which hepatic endocrine sensitivity can be programed in utero and whether the resultant adaptations persist into adulthood is unknown and was therefore the subject of this study. Young adult male sheep born to mothers that were fed either a control diet (i.e.100% of total live weight-maintenance requirements) throughout gestation or 50% of that intake (i.e. nutrient restricted (NR)) from 0 to 95 days gestation and thereafter 100% of requirements (taking into account increasing fetal mass) were entered into the study. All mothers gave birth normally at term, the singleton offspring were weaned at 16 weeks, and then reared at pasture until 3 years of age when their livers were sampled. NR offspring were of similar birth and body weights at 3 years of age when they had disproportionately smaller livers than controls. The abundance of mRNA for GH, prolactin, and IGF-II receptors, plus hepatocyte growth factor and suppressor of cytokine signaling-3 were all lower in livers of NR offspring. In contrast, the abundance of the mitochondrial protein voltage-dependent anion channel and the pro-apoptotic factor Bax were up regulated relative to controls. In conclusion, maternal nutrient restriction in early gestation results in adult offspring with smaller livers. This may be mediated by alterations in both hepatic mitogenic and apoptotic factors.

Animal Nutritional Physiological Phenomena↗

PubMed2006

Increased maternal nutrition stimulates peroxisome proliferator activated receptor-gamma, adiponectin, and leptin messenger ribonucleic acid expression in adipose tissue before birth.

During fetal life, adipose tissue is predominantly comprised of brown or thermogenic adipocytes and there is a transition to white, lipid-storing adipocytes after birth concomitant with the onset of suckling. In pregnancies complicated by gestational diabetes, the fetus is hyperglycemic, has an increased fat mass, and is at increased risk of obesity in later life. In the present study, we have investigated the hypothesis that exposure to increased maternal nutrition during late gestation results in increased expression of genes that regulate adipogenesis and lipogenesis in perirenal fat in fetal sheep. Pregnant ewes were fed either at or approximately 55% above maintenance energy requirements during late pregnancy and quantitative RT-PCR was used to measure peroxisome proliferator-activated receptor gamma, lipoprotein lipase, glycerol-3-phosphate dehydrogenase, adiponectin, and leptin mRNA expression. We report that exposure to metabolic and hormonal signals of increased nutrition before birth results in an increase in the expression of the adipogenic factor, peroxisome proliferator-activated receptor gamma, and in lipoprotein lipase, adiponectin, and leptin mRNA expression in fetal perirenal fat. We propose that an increase in maternal, and hence fetal, nutrition results in a precocial increase in adipogenic, lipogenic, and adipokine gene expression in adipose tissue and that these changes may be important in the development of obesity in later life.

Adiponectin↗

PubMed2006

Prolactin and the expression of suppressor of cytokine signaling-3 in the sheep adrenal gland before birth.

The fetal pituitary-adrenal axis plays a key role in the fetal response to intrauterine stress and in the timing of parturition. The fetal sheep adrenal gland is relatively refractory to stimulation in midgestation (90-120 days) before the prepartum activation, which occurs around 135 days gestation (term=147+/-3 days). The mechanisms underlying the switch from adrenal quiescence to activation are unclear. Therefore, we have investigated the expression of suppressor of cytokine signaling-3 (SOCS-3), a putative inhibitor of tissue growth in the fetal sheep adrenal between 50 and 145 days gestation and in the adrenal of the growth-restricted fetal sheep in late gestation. SOCS-3 is activated by a range of cytokines, including prolactin (PRL), and we have, therefore, determined whether PRL administered in vivo or in vitro stimulates SOCS-3 mRNA expression in the fetal adrenal in late gestation. There was a decrease (P<0.005) in SOCS-3 expression in the fetal adrenal between 54 and 133 days and between 141 and 144 days gestation. Infusion of the dopaminergic agonist, bromocriptine, which suppressed fetal PRL concentrations but did not decrease adrenal SOCS-3 mRNA expression. PRL administration, however, significantly increased adrenal SOCS-3 mRNA expression (P<0.05). Similarly, there was an increase (P<0.05) in SOCS-3 mRNA expression in adrenocortical cells in vitro after exposure to PRL (50 ng/ml). Placental and fetal growth restriction had no effect on SOCS-3 expression in the adrenal during late gestation. In summary, the decrease in the expression of the inhibitor SOCS-3 after 133 days gestation may be permissive for a subsequent increase in fetal adrenal growth before birth. We conclude that factors other than PRL act to maintain adrenal SOCS-3 mRNA expression before 133 days gestation but that acute elevations of PRL can act to upregulate adrenal SOCS-3 expression in the sheep fetus during late gestation.

Adrenal Cortex↗

PubMed2006

Increased maternal nutrition alters development of the appetite-regulating network in the brain.

Individuals exposed to an increased nutrient supply before birth have a high risk of becoming obese children and adults. It has been proposed that exposure of the fetus to high maternal nutrient intake results in permanent changes within the central appetite regulatory network. No studies, however, have investigated the impact of increased maternal nutrition on the appetite regulatory network in species in which this network develops before birth, as in the human. In the present study, pregnant ewes were fed a diet which provided 100% (control, n = 8) or approximately 160% (well-fed, n = 8) of metabolizable energy requirements. Ewes were allowed to lamb spontaneously, and lambs were sacrificed at 30 days of postnatal age. All fat depots were dissected and weighed, and expression of the appetite-regulating neuropeptides and the leptin receptor (OBRb) were determined by in situ hybridization. Lambs of well-fed ewes had higher glucose (Glc) concentrations during early postnatal life (F = 5.93, P<0.01) and a higher relative subcutaneous (s.c.) fat mass at 30 days of age (34.9+/-4.7 g/kg vs. 22.8+/-3.3 g/kg; P<0.05). The hypothalamic expression of pro-opiomelanocortin was higher in lambs of well-fed ewes (0.48+/-0.09 vs. 0.28+/-0.04, P<0.05). In lambs of overnourished mothers, but not in controls, the expression of OBRb was inversely related to total relative fat mass (r2 = 0.50, P = 0.05, n = 8), and the direct relationship between the expression of the central appetite inhibitor CART and fat mass was lost. The expression of neuropeptide Y and AGRP was inversely related to total relative fat mass (NPY, r2 = 0.28, P<0.05; agouti-related peptide, r2 = 0.39, P<0.01). These findings suggest that exposure to increased nutrition before birth alters the responses of the central appetite regulatory system to signals of increased adiposity after birth.

Adipose Tissue↗

PubMed2006

Regulation of leptin synthesis and secretion before birth: implications for the early programming of adult obesity.

A series of epidemiological, clinical and experimental studies have shown that there are associations between the fetal and neonatal nutritional environment and the amount and distribution of adipose tissue in adult life. This review considers the evidence for these relationships and discusses the potential impact of the prenatal nutritional experience on the development of the endocrine and neuroendocrine systems that regulate energy balance, with a particular emphasis on the role of the adipocyte-derived hormone, leptin. In the rodent, leptin derived from the mother may exert an important influence on the development of the appetite regulatory neural network and on the subsequent regulation of leptin synthesis and the risk for obesity in the offspring. In species such as the human and sheep, there is also recent evidence that the synthesis and secretion of adipocyte-derived hormones, such as leptin, are regulated in fetal life. Furthermore, the hypothalamic neuropeptides that regulate energy intake and expenditure in adult life are also present within the fetal brain and may be regulated by the prevailing level of maternal and hence fetal nutrient and hormonal signals, including leptin. This work is important in determining those initiating mechanisms within the 'fat-brain' axis in early life that precede the development of adult obesity.

Adipocytes↗

PubMed2005

Periconceptional nutrition and the relationship between maternal body weight changes in the periconceptional period and feto-placental growth in the sheep.

Recent studies in the sheep have shown that maternal undernutrition during the periconceptional period, when the nutrient demands of the embryo are minimal, can alter the subsequent development of the metabolic, endocrine and cardiovascular systems and that these effects may, in part, depend on embryo number. We have tested the hypotheses that there are relationships between maternal weight or body condition at the time of conception and feto-placental growth during the first 55 days of pregnancy, and that periconceptional undernutrition has a differential effect on these relationships in singleton and twin pregnancies. We have investigated the effect of periconceptional undernutrition in the ewe (control n= 24, restricted at 70% of control feed allowance, PCUN n= 21) from 45 days prior to mating until 7 days after mating on placental and fetal weight and on placental histology in singleton and twin pregnancies at 53-56 days' gestation, i.e. during the period of maximal placental growth. In control, but not PCUN ewes carrying singleton pregnancies, there were direct relationships between maternal weight gain during the periconceptional period and uteroplacental weights at 53-56 days' gestation. There were direct relationships, however, between placental and fetal weights in both control and PCUN singleton pregnancies. In contrast to the singletons, in control twin pregnancies, there was no effect of maternal weight gain in the periconceptional period on any measure of uteroplacental growth, and there was also no relationship between placental and fetal weight. This lack of a relationship may be related to the increased uteroplacental weight and mean placentome weight in the twin pregnancies (control singletons: 2.45 +/- 0.18 g; control twins: 4.10 +/- 0.62 g). In the PCUN group, however, a greater weight loss between the start of the feeding regime and post mortem at approximately day 55, was associated with a larger placenta and fetus, and the direct relationship between placental and fetal mass was restored. In summary, the present study has demonstrated that there are important relationships between maternal weight gain during the periconceptional period and feto-placental growth during the first 56 days of pregnancy, and that periconceptional undernutrition has a differential effect on these relationships in singleton and twin pregnancies. In singleton pregnancies, periconceptional undernutrition disrupts the relationship between maternal weight gain during the periconceptional period and uteroplacental growth, and in twin pregnancies periconceptional undernutrition results in the emergence of an inverse relationship between maternal weight gain during early pregnancy and uteroplacental growth and a dependence of fetal growth on placental growth. These changes highlight the importance of the periconceptional environment in setting the placental and fetal growth trajectories, and have implications for the programmed development of the metabolic, cardiovascular and endocrine systems of the fetus and adult.

Animals↗

PubMed2005

Impact of glucose infusion on the structural and functional characteristics of adipose tissue and on hypothalamic gene expression for appetite regulatory neuropeptides in the sheep fetus during late gestation.

In the present study, our aim was to determine whether intrafetal glucose infusion increases fetal adiposity, synthesis and secretion of leptin and regulates gene expression of the 'appetite regulatory' neuropeptides neuropepetide Y (NPY), agouti-related peptide (AGRP), pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) and receptors (leptin receptor (OB-Rb) and melancortin 3 receptor (MC3R)) within the fetal hypothalamus. Glucose (50% dextrose in saline) or saline was infused (7.5 ml h(-1)) into fetal sheep between 130 and 140 days gestation (term = 150 +/- 3 days gestation). Glucose infusion increased circulating glucose and insulin concentrations, mean lipid locule size (532.8 +/- 3.3 microm2 versus 456.7 +/- 14.8 microm2) and total unilocular fat mass (11.7 +/- 0.6 g versus 8.9 +/- 0.6 g) of the perirenal fat depot. The expression of OB-Rb mRNA was higher in the ventromedial nucleus compared to the arcuate nucleus of the hypothalamus in both glucose and saline infused fetuses (F= 8.04; P < 0.01) and there was a positive correlation between expression of OB-Rb and MC3R mRNA in the arcuate nucleus (r= 0.81; P < 0.005). Glucose infusion increased mRNA expression for POMC, but not for the anorectic neuropeptide CART, or the orexigenic neuropeptides NPY and AGRP, in the arcuate nucleus of the fetal hypothalamus. These findings demonstrate that increased circulating glucose and insulin regulate gene expression of the neuropeptides within the fetal hypothalamus that are part of the neural network regulating energy balance in adult life.

Adipose Tissue↗

PubMed2004

Impact of periconceptional nutrition on maternal and fetal leptin and fetal adiposity in singleton and twin pregnancies.

It has been proposed that maternal nutrient restriction may alter the functional development of the adipocyte and the synthesis and secretion of the adipocyte-derived hormone, leptin, before birth. We have investigated the effects of restricted periconceptional undernutrition and/or restricted gestational nutrition on fetal plasma leptin concentrations and fetal adiposity in late gestation. There was no effect of either restricted periconceptional or gestational nutrition on maternal or fetal plasma leptin concentrations in singleton or twin pregnancies during late gestation. In ewes carrying twins, but not singletons, maternal plasma leptin concentrations in late gestation were directly related to the change in ewe weight that occurred during the 60 days before mating [maternal leptin = 0.9 (change in ewe weight) + 7.8; r = 0.6, P < 0.05]. In twin, but not singleton, pregnancies, there was also a significant relationship between maternal and fetal leptin concentrations (maternal leptin = 0.5 fetal leptin + 4.2, r = 0.63, P < 0.005). The relative mass of perirenal fat was also significantly increased in twin fetal sheep in the control-restricted group (6.0 +/- 0.5) compared with the other nutritional groups (control-control: 4.1 +/- 0.4; restricted-restricted: 4.4 +/- 0.4; restricted-control: 4.3 +/- 0.3). In conclusion, the impact of maternal undernutrition on maternal plasma leptin concentrations during late gestation is dependent on fetal number. Furthermore, we have found that there is an increased fetal adiposity in the twins of ewes that experienced restricted nutrition throughout gestation, and this may be important in the programming of postnatal adiposity.

Adipose Tissue↗

PubMed2004

Differential actions of metyrapone on the fetal pituitary-adrenal axis in the sheep fetus in late gestation.

It is not clear if an increase in intra-adrenal cortisol is required to mediate the actions of adrenocorticotropic hormone (ACTH) on adrenal growth and steroidogenesis during the prepartum stimulation of the fetal pituitary-adrenal axis. We infused metyrapone, a competitive inhibitor of cortisol biosynthesis, into fetal sheep between 125 and 140 days of gestation (term = 147 +/- 3 days) and measured fetal plasma cortisol, 11-desoxycortisol, and ACTH; pituitary pro-opiomelanocortin mRNA and adrenal expression of ACTH receptor (melanocortin type 2 receptor), steroidogenic acute regulatory protein (StAR), 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2), cytochrome P450 cholesterol side-chain cleavage (CYP11A1), cytochrome P450 17-hydroxylase (CYP17), 3beta-hydroxysteroid dehydrogenase, and cytochrome P450 21-hydroxylase mRNA; and StAR protein in the fetal adrenal gland. Plasma ACTH and 11-desoxycortisol concentrations were higher (P < 0.05), whereas plasma cortisol concentrations were not significantly different in metyrapone- compared with vehicle-infused fetuses. The ratio of plasma cortisol to ACTH concentrations was higher (P < 0.0001) between 136 and 140 days than between 120 and 135 days of gestation in both metyrapone- and vehicle-infused fetuses. The combined adrenal weight and adrenocortical thickness were greater (P < 0.001), and cell density was lower (P < 0.01), in the zona fasciculata of adrenals from the metyrapone-infused group. Adrenal StAR mRNA expression was lower (P < 0.05), whereas the levels of mature StAR protein (30 kDa) were higher (P < 0.05), in the metyrapone-infused fetuses. In addition, adrenal mRNA expression of 11betaHSD2, CYP11A1, and CYP17 were higher (P < 0.05) in the metyrapone-infused fetuses. Thus, metyrapone administration may represent a unique model that allows the investigation of dissociation of the relative actions of ACTH and cortisol on fetal adrenal steroidogenesis and growth during late gestation.

11-beta-Hydroxysteroid Dehydrogenase Type 2↗

PubMed2004

Nutritional manipulation of fetal adipose tissue deposition and uncoupling protein 1 messenger RNA abundance in the sheep: differential effects of timing and duration.

A range of epidemiological and experimental studies have indicated that suboptimal nutrition at different stages of gestation is associated with an increased prevalence of adult hypertension, cardiovascular disease, and obesity. The timing of prenatal nutrient restriction is important in determining postnatal outcomes-including obesity. The present study, aimed to determine the extent to which fetal adiposity and expression of the key thermogenic protein, uncoupling protein (UCP)1, are altered by restriction of maternal nutrient intake imposed during four different periods, starting from before conception. Maternal nutrient intake was restricted from 60 days before until 8 days after mating (periconceptional nutrient restriction; R-C), from 60 days before mating and throughout gestation (R-R), from 8 days gestation until term (C-R), or from 115 days gestation until term. Fetal perirenal adipose tissue (PAT) was sampled near to term at approximately 143 days. UCP1 mRNA, but not protein, abundance in PAT was increased in fetuses in the R-R group (C-C 63 +/- 18; R-C 83 +/- 43; C-R 103 +/- 38; R-R 167 +/- 50 arbitrary units (P < 0.05)). In contrast, the abundance of UCP1 mRNA, but not protein, in fetal PAT was decreased when maternal nutrition was restricted from 115 days gestation. The major effect of maternal nutrient restriction on adipose tissue deposition occurred in the C-R group, in which the proportion of fetal fat was doubled, whereas maternal nutrient restriction from 115 days gestation reduced fetal fat deposition. In conclusion, there are differential effects of maternal and therefore fetal nutrient restriction on UCP1 mRNA expression and fetal fat mass and these effects are dependent on the timing and duration of nutrient restriction.

Adipose Tissue↗

PubMed2004

Effects of leptin on fetal plasma adrenocorticotropic hormone and cortisol concentrations and the timing of parturition in the sheep.

We investigated whether leptin can suppress the prepartum activation of the fetal hypothalamus-pituitary-adrenal (HPA) axis and delay the timing of parturition in the sheep. First, we investigated the effects of a 4-day intravascular infusion of recombinant ovine leptin (n = 7) or saline (n = 6) on fetal plasma adrenocorticotropic hormone (ACTH) and cortisol concentrations, starting from 136 days gestation (i.e., at the onset of the prepartum activation of the fetal HPA axis. The effects of a continuous intrafetal infusion of leptin (n = 7) or saline (n = 5) from 144 days gestation on fetal plasma ACTH and cortisol concentrations and the timing of delivery were also determined in a separate study. There was an increase in fetal plasma ACTH (P < 0.01) and cortisol (P < 0.001) concentrations when saline was infused between 136-137 and 140-141 days gestation. Plasma ACTH and cortisol concentrations did not rise, however, when leptin was infused during this period of gestation. When leptin was infused after 144 days gestation, there was no effect of a 4- to 5-fold increase in circulating leptin on fetal ACTH concentrations. In contrast, leptin infusion from 144 days gestation suppressed (P < 0.05) fetal plasma cortisol concentrations by around 40% between 90 and 42 h before delivery. There was no difference, however, in the length of gestation between the saline- and leptin-infused groups (saline infused, 150.2 +/- 0.5 days; leptin infused, 149.8 +/- 1.0 days). In saline-infused fetuses, there was a significant negative relationship between the plasma concentrations of cortisol (y) and leptin (x) between 138 and 146 days gestation (y = 81.4 - 7.7x, r = 0.38, P < 0.005). This study provides evidence for an endocrine negative feedback loop between leptin and the HPA axis in fetal life.

Adrenocorticotropic Hormone↗

PubMed2004

Postnatal ontogeny of glucose homeostasis and insulin action in sheep.

Glucose tolerance declines with maturation and aging in several species, but the time of onset and extent of changes in insulin sensitivity and insulin secretion and their contribution to changes in glucose tolerance are unclear. We therefore determined the effect of maturation on glucose tolerance, insulin secretion, and insulin sensitivity in a longitudinal study of male and female sheep from preweaning to adulthood, and whether these measures were related across age. Glucose tolerance was assessed by intravenous glucose tolerance test (IVGTT, 0.25 g glucose/kg), insulin secretion as the integrated insulin concentration during IVGTT, and insulin sensitivity by hyperinsulinemic-euglycemic clamp (2 mU insulin.kg(-1).min(-1)). Glucose tolerance, relative insulin secretion, and insulin sensitivity each decreased with age (P < 0.001). The disposition index, the product of insulin sensitivity, and various measures of insulin secretion during fasting or IVGTT also decreased with age (P < 0.001). Glucose tolerance in young adult sheep was independently predicted by insulin sensitivity (P = 0.012) and by insulin secretion relative to integrated glucose during IVGTT (P = 0.005). Relative insulin secretion before weaning was correlated positively with that in the adult (P = 0.023), whereas glucose tolerance, insulin sensitivity, and disposition indexes in the adult did not correlate with those at earlier ages. We conclude that glucose tolerance declines between the first month of life and early adulthood in the sheep, reflecting decreasing insulin sensitivity and absence of compensatory insulin secretion. Nevertheless, the capacity for insulin secretion in the adult reflects that early in life, suggesting that it is determined genetically or by persistent influences of the perinatal environment.

Age Factors↗

PubMed2004

Prenatal programming of postnatal obesity: fetal nutrition and the regulation of leptin synthesis and secretion before birth.

Exposure to either an increased or decreased level of intrauterine nutrition can result in an increase in adiposity and in circulating leptin concentrations in later life. In animals such as the sheep and pig in which fat is deposited before birth, leptin is synthesised in fetal adipose tissue and is present in the fetal circulation throughout late gestation. In the sheep a moderate increase or decrease in the level of maternal nutrition does not alter fetal plasma leptin concentrations, but there is evidence that chronic fetal hyperglycaemia and hyperinsulinaemia increase fetal fat mass and leptin synthesis within fetal fat depots. Importantly, there is a positive relationship between the relative mass of the 'unilocular' component of fetal perirenal and interscapular adipose tissue and circulating fetal leptin concentrations in the sheep. Thus, as in the neonate and adult, circulating leptin concentrations may be a signal of fat mass in fetal life. There is also evidence that leptin can act to regulate the lipid storage, leptin synthetic capacity and potential thermogenic functions of fat before birth. Thus, leptin may act as a signal of energy supply and have a 'lipostatic' role before birth. Future studies are clearly required to determine whether the intrauterine and early postnatal nutrient environment programme the endocrine feedback loop between adipose tissue and the central and peripheral neuroendocrine systems that regulate energy balance, resulting in an enhanced risk of obesity in adult life.

Adipose Tissue↗

PubMed2004

Metyrapone infusion stimulates adrenal growth without activating the cell cycle or the IGF system in the late gestation fetal sheep.

Recently, we have demonstrated that administration of metyrapone, to suppress cortisol synthesis and decrease negative feedback at the pituitary, results in an increase in circulating ACTH and adrenal growth in the late gestation sheep fetus. In these studies, we demonstrated a 2-fold increase in adrenocortical growth using morphometric techniques. To elucidate the potential molecular mechanisms leading to the increase in adrenal growth, we examined adrenal expression of the cell cycle regulatory proteins (cyclin D1) and cyclin-kinase inhibitory proteins (p16ink, p21Cip), and insulin-like growth factor-II (IGF-II), IGF-binding protein 2 (IGFBP-2) and IGF-I type 1 Receptor (IGF1R) from fetuses infused with metyrapone or vehicle for 15 days. There was a significant decrease in adrenal expression of cyclin D1 in metyrapone-(472.0 +/- 29.7) compared with vehicle-infused (662.7 +/- 29.2) fetuses. There was no significant difference, however, in the adrenal expression of the cyclin-kinase inhibitory proteins (p16ink or p21Cip) or in the IGF system (IGF-II, IGFBP-2 or IGF1R) mRNA between metyrapone- and vehicle-infused. In summary, in this model of metyrapone-activated adrenal cortical hypertrophy, growth occurs with a suppression of the rate-limiting cell cycle protein and without activation of the IGF system.

Adrenal Glands↗

PubMed2004

Early embryonic environment, the fetal pituitary-adrenal axis and the timing of parturition.

It is well established in the sheep, that the normal timing of parturition is dependent on a prepartum activation of the fetal pituitary-adrenal axis. We have recently demonstrated for the first time that embryo number, embryo sex, and alterations in the environment of the early embryo, including exposure to maternal undernutrition during the periconceptional period, alter the timing and level of activation of the pituitary-adrenal axis in the sheep fetus during late gestation. There is a delay in activation of the fetal HPA axis in twin fetuses and we speculate that the diminished adrenocortical responsiveness in the twin fetus may be an adaptive response, which counters the impact of the potential enhanced intrauterine stress experienced by a twin fetus, thereby reducing the possibility of preterm delivery. We have also reported that a moderate restriction of maternal nutrition to during the periconceptional period (from 60 days before and for one week after conception) resulted in an earlier activation of the pituitary-adrenal axis of twin, but not singleton, fetuses during late gestation. A series of studies using assisted reproductive technologies have also found that perturbation of the early embryonic environment results in a dysregulation of placental and fetal growth and development and in the timing of normal parturition. In summary, after several decades of work focussed on events in late gestation associated with the prepartum activation and stress responsiveness of the fetal HPA axis, our recent studies indicate that the environment of the early embryo may have a significant role to play in determining the timing and level of the prepartum activation of this axis and potentially on the functional capacity of the axis to respond to acute or chronic stress in later life.

Animals↗

PubMed2004

Appetite regulatory neuropeptides are expressed in the sheep hypothalamus before birth.

In the adult, a hypothalamic neural network acts to maintain energy balance in response to nutritional feedback from the periphery. Although there is an immediate requirement for this system to be functional at birth, it is unknown whether the components of this central neural network are expressed in the developing brain before birth. We therefore examined in the fetal sheep hypothalamus during late gestation gene expression for leptin receptor (OB-Rb) and neuropeptides that regulate energy balance in the adult. Brains were collected from fetal sheep at 110 days (n = 12) and 140 days of gestation (n = 5) (term = 150 days) and gene expression was detected in all hypothalami using in situ hybridization with radiolabelled riboprobes for OB-Rb, neuropeptide Y (NPY), agouti-related peptide, pro-opiomelanocortin and cocaine- and amphetamine-regulated transcript (CART). All mRNAs were expressed in the arcuate nucleus of fetuses at both time points. Additional sites of mRNA expression were the dorsomedial hypothalamus (DMH) for NPY, the paraventricular nucleus (PVN), ventromedial hypothalamus (VMH) and lateral hypothalamic area for CART, and the DMH, PVN and VMH for OB-Rb. We have therefore demonstrated that adult-like localization of gene expression for OB-Rb and key appetite regulatory neuropeptides is established in the ovine hypothalamus before birth. Thus, the fetus possesses a central appetite regulatory neural network with the potential to respond to changes in nutrient supply, which could impact on energy balance regulation both before and after birth.

Age Factors↗

PubMed2003

The effect of intrafetal infusion of metyrapone on arterial blood pressure and on the arterial blood pressure response to angiotensin II in the sheep fetus during late gestation.

While the impact of exogenous glucocorticoids on the fetal cardiovascular system has been well defined, relatively few studies have characterised the role of endogenous fetal glucocorticoids in the regulation of arterial blood pressure (BP) during late gestation. We have therefore infused metyrapone, an inhibitor of cortisol biosynthesis, into fetal sheep from 125 days gestation (when fetal cortisol concentrations are low) and from 137 days gestation (when fetal cortisol concentrations are increasing) and measured fetal plasma cortisol, 11-desoxycortisol and ACTH, fetal systolic, diastolic and mean arterial BP, heart rate, and the fetal BP responses to increasing doses of angiotensin II (AII). At 125 days gestation, there was a significant increase in fetal plasma ACTH and 11-desoxycortisol by 24 h after (+24 h) the start of the metyrapone infusion, and plasma cortisol concentrations were not different at +24 h when compared with pre-infusion values. Whilst the initial fall in circulating cortisol concentrations may have been transient, systolic, diastolic and mean arterial BP were ~5-6 mmHg lower (P < 0.05) in metyrapone- than in vehicle-infused fetuses at 24-48 h after the start of the infusion. When metyrapone was infused from 137/138 days gestation, there was a significant decrease in plasma cortisol concentrations by +6 h, which was followed by an increase back to pre-infusion values. While cortisol concentrations decreased, there was no change in fetal mean arterial BP during the first 24 h after the start of metyrapone infusion. Mean fetal arterial BP values at 137-139 days gestation were not different in fetuses that had been infused with either vehicle or metyrapone from 125 days gestation or with metyrapone from 137/138 days gestation. At 137-139 days gestation, however, arterial BP responses to increasing doses of AII were significantly blunted in fetuses that had been infused with metyrapone from 125 days gestation, when compared with fetuses that had been infused with metyrapone from 137/138 days gestation or with vehicle from 125 days gestation. The dissociation of the gestational age increase in arterial BP and the effects of intrafetal AII on fetal arterial BP indicates that increase in fetal BP with gestational age is not entirely a result of an increased vascular responsiveness to endogenous AII. Furthermore there may be a critical window during late gestation when the actions of cortisol contribute to the development of vascular responsiveness to AII.

Adrenocorticotropic Hormone↗

PubMed2003

Determinants of fetal leptin synthesis, fat mass, and circulating leptin concentrations in well-nourished ewes in late pregnancy.

We have investigated the factors regulating leptin synthesis, fat deposition, and circulating leptin concentrations in fetuses of well nourished ewes in late pregnancy. Vascular catheters were surgically inserted in 17 pregnant ewes and their fetuses at 103-120 d gestation (term = 147 +/- 3 d). Ewes were fed a diet providing either 100% (control; n = 9) or approximately 155% (well fed; n = 8) of the maintenance energy requirements and fetal perirenal and interscapular fat depots were collected at 139-141 d gestation. There was a significant relationship between the relative mass of fetal unilocular fat and fetal glucose (relative mass of unilocular fat, 1.14; fetal glucose, +0.16; r = 0.50; P < 0.04; n = 17), but not insulin, concentrations in the control and well-fed groups. In contrast to the controls, there was a positive relationship between the relative abundance of leptin mRNA and fetal insulin, but not glucose, concentrations in fetal perirenal adipose tissue in the well-fed group. A moderate increase in maternal nutrition also resulted in a strong reciprocal relationship between uncoupling protein 1 and leptin expression in fetal perirenal adipose tissue in late gestation (well-fed group: uncoupling protein 1 mRNA:18S rRNA, -0.51; leptin mRNA:beta-actin mRNA, +1.53; r = 0.80; P < 0.02; n = 8). These studies provide evidence that fetal glucose and insulin differentially regulate fetal fat deposition and leptin mRNA expression within the fetal perirenal fat depot in the well nourished animal during late gestation.

Adipose Tissue↗