Fetal leptin is a signal of fat mass independent of maternal nutrition in ewes fed at or above maintenance energy requirements

In adults, circulating leptin concentrations are dependent on body fat content and on current nutritional status. However, the relationships among maternal nutrient intake, fetal adiposity, and circulating leptin concentrations before birth are unknown. We investigated the effects of an increase in nutrient intake in the pregnant ewe on fetal adiposity and plasma leptin concentrations during late gestation. Between 115 and 139-141 days gestation (term = 147 +/- 3 days gestation), ewes were fed a diet calculated to provide either maintenance (control, n = 6) or approximately 155% of maintenance requirements (well-fed, n = 8). The fetal fat depots (perirenal and interscapular) were dissected, and the relative proportion of unilocular and multilocular adipocytes in each depot was determined. Maternal plasma glucose and leptin concentrations were significantly increased in well-fed ewes. Fetal plasma glucose concentrations were also higher in the well-fed group (115-139 days gestation: control, 1.65 +/- 0.14 mmol/L; well-fed, 2.00 +/- 0.14 mmol/L; F = 5.76, P < 0.04). There was no effect of increasing maternal feed intake on total fat mass, the relative mass of unilocular fat, or fetal plasma leptin concentrations (115-139 days gestation: control, 5.2 +/- 0.8 ng/ml; well-fed, 4.7 +/- 0.7 ng/ml). However, in both the control and well-fed groups fetal plasma leptin concentrations (y) were positively correlated with the relative mass of unilocular fat (x): y = 1.51x + 1.70; (R = 0.76, P < 0.01). Thus, fetal leptin may play a role as a signal of unilocular fat mass in the fetus when maternal nutrient intake is at or above maintenance requirements.     

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.     

Effect of maternal feed restriction during pregnancy on glucose tolerance in the adult guinea pig

Maternal nutrient restriction and impaired fetal growth are associated with postnatal insulin resistance, hyperinsulinemia, and glucose intolerance in humans but not consistently in other species, such as the rat or sheep. We therefore determined the effect of mild (85% ad libitum intake/kg body wt) or moderate (70% ad libitum intake/kg body wt) maternal feed restriction throughout pregnancy on glucose and insulin responses to an intravenous glucose tolerance test (IVGTT) in the young adult guinea pig. Maternal feed restriction reduced birth weight (mild and moderate: both P < 0.02) in male offspring. Moderate restriction increased plasma glucose area under the curve (P < 0.04) and decreased the glucose tolerance index (K(G)) (P < 0.02) during the IVGTT in male offspring compared with those of mildly restricted but not of ad libitum-fed mothers. Moderate restriction increased fasting plasma insulin (P < 0.04, adjusted for litter size) and the insulin response to IVGTT (P < 0.001), and both moderate and mild restriction increased the insulin-to-glucose ratio during the IVGTT (P < 0.003 and P < 0.02) in male offspring. When offspring were classed into tertiles according to birth weight, glucose tolerance was not altered, but fasting insulin concentrations were increased in low compared with medium birth weight males (P < 0.03). The insulin-to-glucose ratio throughout the IVGTT was increased in low compared with medium (P < 0.01) or high (P < 0.05) birth weight males. Thus maternal feed restriction in the guinea pig restricts fetal growth and causes hyperinsulinemia in young adult male offspring, suggestive of insulin resistance. These findings suggest that mild to moderate prenatal perturbation programs postnatal glucose homeostasis adversely in the guinea pig, as in the human.     

The effect of maternal undernutrition on the growth and development of the guinea pig placenta.

Fetal growth is known to be correlated with the size of the placenta and the exchange surface area. Reduction in the growth of the materno-fetal exchange surface areas may be a mechanism by which the effects of maternal undernutrition on fetal growth are mediated. In the compact placenta of the guinea pig the exchange surface is equivalent to the peripheral labyrinth. The effect of a 40% reduction in maternal feed intake on the growth of the peripheral labyrinth was investigated in pregnant guinea pigs between gestational days 25 and 65. Fetal and placental weights were significantly reduced in the last trimester by 32% and 38% respectively (P < 0.01). Placental efficiency in early gestation was significantly impaired in restricted animals but equivalent to ad lib. fed controls by the last trimester. The volume of the peripheral labyrinth increased as a percentage of the total placental volume with gestational age. Restricted placentae tended to be composed of a smaller volume of peripheral labyrinth tissue in early gestation. It is suggested that maternal undernutrition results in an impaired or delayed expansion of the peripheral labyrinth in early gestation causing a reduction in placental efficiency. By the last trimester the weight of the peripheral labyrinth of restricted animals was reduced by 33% (P < 0.05). The weight of the peripheral labyrinth was also significantly correlated with fetal weight is limited by the size of the peripheral labyrinth in the later stages of gestation.     

Maternal-fetal hepatic and placental metabolome profiles are associated with reduced fetal growth in a rat model of maternal obesity

Introduction

Maternal obesity is associated with a range of pregnancy complications, including fetal growth restriction (FGR), whereby a fetus fails to reach its genetically determined growth. Placental insufficiency and reduced nutrient transport play a role in the onset of FGR.

Objectives

Metabolomic profiling was used to reveal altered maternal and fetal metabolic pathways in a model of diet induced obesity during pregnancy, leading to reduced fetal growth.

Methods

We examined the metabolome of maternal and fetal livers, and placenta following a high fat and salt intake. Sprague–Dawley rats were assigned to (a) control diet (CD; 1 % salt, 10 % kcal from fat), (b) high salt diet (SD; 4 % salt, 10 % kcal from fat), (c) high fat diet (HF; 1 % salt, 45 % kcal from fat) or (d) high-fat high-salt diet (HFSD; 4 % salt, 45 % kcal from fat) 21 days prior to pregnancy and during gestation. Metabolites from maternal and fetal livers, and placenta were identified using gas and liquid chromatography combined with mass spectrometry.

Results

Maternal HF intake resulted in reduced fetal weight. Altered metabolite profiles were observed in the HF maternal and fetal liver, and placenta. Polyunsaturated fatty acid metabolism was significantly altered in maternal and fetal liver by maternal fat intake.

Conclusion

Excess of linoleic and α-linoleic acid (essential fatty acids) may be detrimental during placentation and associated with a reduction in fetal weight. Additionally, maternal, placental and fetal response to increased fat consumption seems likely to involve palmitoleic acid utilization as an adaptive response during maternal obesity.

     

Dietary regulation of maternal and fetal cholesterol metabolism in the guinea pig

Studies to determine the effects of pre-natal interventions on maternal and fetal cholesterol homeostasis were carried out in the guinea pig. Guinea pig dams were fed either non-purified guinea pig diet or diet supplemented with either 1.1% of the bile acid binding resin cholestyramine or 0.25% cholesterol. Whole body rates of endogenous cholesterol synthesis were determined by quantitation of [3H]water incorporation into digitonin precipitable sterols in non-pregnant animals and at 40 and 60 days of gestation in the dam and fetus. Maternal hepatic cholesterol synthesis was reduced 87% by dietary cholesterol and was increased 3.5-fold with cholestyramine feeding. Fetal hepatic and peripheral tissue cholesterol synthesis rates peaked at 40 days gestation when peripheral tissue cholesterol synthesis was 5.7-fold higher and hepatic synthesis 6.2-fold greater than the near adult levels observed at 60 days. Cholesterol synthesis in the fetus was relatively insensitive to dietary manipulations; however, maternal cholestyramine treatment did result in a 1.4-fold increase in fetal carcass cholesterol synthesis at 60 days gestation. These data demonstrate that maternal cholesterogenic systems maintain responsiveness to dietary regulation during pregnancy; whereas fetal cholesterol homeostasis is relatively insensitive to dietary cholesterol throughout gestation yet may respond to induction by maternal cholestyramine treatment during the late gestation period.     

Effects of feed restriction during organogenesis on embryo-fetal development in rabbit

BACKGROUND: Appropriate maternal nutrition and body weight gain during pregnancy is well established as a major factor in healthy prenatal development in humans. Given the role of nutrition and body weight gain in normal development, pharmaceuticals intended to reduce appetite and promote weight loss will generate developmental toxicity data that may be challenging to interpret. To aid with this, the effects of feed restriction, and subsequent reduction in maternal body weight gain, on embryo-fetal development was investigated in the rabbit. METHODS: Groups of 15 pregnant New Zealand White rabbits were offered 150 (control), 110, 75, 55, 35, and 15 g feed/day from gestation day (GD) 7-19. Cesarean sections were carried out on GD 29 and fetuses were examined for external, visceral, and skeletal development. RESULTS: Maternal body weights at the end of the feed restriction period (GD 20) were 0.97, 0.98, 0.93, 0.94, and 0.86 x control for the 110, 75, 55, 35, and 15 g feed/day groups, respectively. Only at 15 g feed/day was there a net maternal body weight loss (the GD 20 body weight was 0.93 x the GD 6 body weight) at the end of the feed restriction period. Six does aborted in the 15 g feed/day group; there were no other abortions associated with feed restriction. Fetal body weight was significantly reduced at 75, 55, 35, and 15 g feed/day (0.95, 0.90, 0.86, and 0.84 x control, respectively). There were no external or visceral malformations or variations, and no skeletal malformations associated with feed restriction. The incidence of fetuses with sternebrae 5 or 6 unossified was increased at feed levels < or = 75 g/day. At a feed level of 35 g/day there was an increase in unossified metatarsals and metacarpals, and an increase in the number of fetuses with a reduced number of caudal vertebrae ossified. Although these findings were not increased at a feed level of 15 g/day, the lack of dose response was likely due to increased abortion and subsequent decrease in fetuses available for evaluation at 15 g feed/day. CONCLUSION: These data demonstrate that feed restriction to feed levels that produce substantial reductions in maternal body weight gain can result in developmental toxicity expressed by abortion, reduced fetal weight, and alterations in ossification. Abortion only occurred when feed was restricted to an amount that produced maternal body weight loss (15 g feed/day) whereas reduced fetal weight and increased incidence of fetuses with unossified sternebrae, metatarsals, metacarpals, or caudal vertebrae were noted at feed levels of < or = 75 g/day. There were no fetal malformations associated with feed restriction.     

The effects of maternal undernutrition on maternal and fetal serum insulin-like growth factors, thyroid hormones and cortisol in the guinea pig.

The insulin-like growth factors (IGF-I and -II) are potential mediators of the effects of maternal undernutrition on fetal growth and muscle development. The effects of a 40% reduction in maternal feed intake on serum levels of the IGFs, the thyroid hormones and cortisol, were investigated for the last two trimesters (day 25 to birth). This level of undernutrition is known to cause a 35% reduction in fetal and placental weights, and a 20-25% reduction in muscle fibre number. Maternal IGF-I level was greater than non-pregnant levels on day 25 gestation, in both control and restricted dams, and declined with gestational age. The increase in IGF-I level in the 40% restricted group was approximately two-thirds that of control animals. Fetal serum IGF-I was also reduced in undernourished fetuses throughout gestation. Maternal IGF-II did not change with gestational age and was unaffected by undernutrition. Fetal IGF-II reached a peak at day 55 of gestation, this peak was greatly diminished by maternal feed restriction. Both IGF-I and IGF-II tended to be related to fetal, placental and muscle weights at day 65 of gestation. Thyroid hormone concentration declined in maternal serum and increased in fetal serum with increasing gestational age. Levels were not significantly affected by undernutrition. Both triiodothyronine (T3) and thyroxine (T4) were correlated with IGF-I in maternal serum (P < 0.05), but not in fetal serum. Cortisol levels were elevated by undernutrition in both maternal and fetal serum, and increased with gestational age. Cortisol was inversely correlated with serum IGF-I in both maternal and fetal serum. Maternal serum IGF-I may mediate the effects of undernutrition on fetal growth by affecting the growth and establishment of the feto-placental unit in mid-gestation. Fetal IGF-I may mediate the effects on muscle growth, whereas IGF-II seems to be related to hepatic glycogen deposition. Cortisol may play a role via its effect on the IGFs, but the thyroid hormones are unlikely to be important until the late gestation/early postnatal period.     

Arginine nutrition and fetal brown adipose tissue development in nutrient-restricted sheep

Intrauterine growth restriction is a significant problem worldwide, resulting in increased rates of neonatal morbidity and mortality, as well as increased risks for metabolic and cardiovascular disease. The present study investigated the role of maternal undernutrition and l-arginine administration on fetal growth and development. Embryo transfer was utilized to generate genetically similar singleton pregnancies. On Day 35 of gestation, ewes were assigned to receive either 50 or 100% of their nutritional requirements. Ewes received i.v. injections of either saline or l-arginine three times daily from Day 100 to Day 125. Fetal growth was assessed at necropsy on Day 125. Maternal dietary manipulation altered circulating concentrations of leptin, progesterone, and amino acids in maternal plasma. Fetal weight was reduced in nutrient-restricted ewes on Day 125 compared with 100% fed ewes. Compared with saline-treated underfed ewes, maternal l-arginine administration did not affect fetal weight but increased weight of the fetal pancreas by 32% and fetal peri-renal brown adipose tissue mass by 48%. These results indicate that l-arginine administration enhanced fetal pancreatic and brown adipose tissue development. The postnatal effects of increased pancreatic and brown adipose tissue growth warrant further study.     

Arginine nutrition and fetal brown adipose tissue development in diet-induced obese sheep

The global incidence of human obesity has more than doubled over the past three decades. An ovine model of obesity was developed to determine effects of maternal obesity and arginine supplementation on maternal, placental, and fetal parameters of growth, health, and well being. One-hundred-twenty days prior to embryo transfer, ewes were fed either ad libitum (n?=?10) to induce obesity or 100% National Research Council-recommended nutrient requirements (n?=?10) as controls. Embryos from superovulated ewes with normal body condition were transferred to the uterus of control-fed and obese ewes on day 5.5 post-estrus to generate genetically similar singleton pregnancies. Beginning on day 100 of gestation, obese ewes received intravenous administration of saline or L-arginine-HCl three times daily (81?mg arginine/kg?body?weight/day) to day 125, whereas control-fed ewes received saline. Fetal growth was assessed at necropsy on day 125. Maternal obesity increased (1) percentages of maternal and fetal carcass lipids and (2) concentrations of leptin, insulin, glucose, glutamate, leucine, lysine and threonine in maternal plasma while reducing (1) concentrations of progesterone, glycine and serine in maternal plasma and (2) amniotic and allantoic fluid volumes. Administration of L-arginine to obese ewes increased arginine and ornithine concentrations in maternal and fetal plasma, amniotic fluid volume, protein content in maternal carcass, and fetal brown adipose tissue (+60%), while reducing maternal lipid content and circulating leptin levels. Fetal or placental weight did not differ among treatments. Results indicate that arginine treatment beneficially reduces maternal adiposity and enhances fetal brown adipose tissue development in obese ewes.     

Nutritional regulation of fetal growth and implications for productive life in ruminants

The maternal nutritional and metabolic environment is critical in determining not only the reproductive success but also the long-term health and viability of the offspring. Changes in maternal diet at defined stages of gestation coincident with different stages of development can have pronounced effects on organ and tissue function in later life. This includes adipose tissue for which differential effects are observed between brown and white adipose tissues. One early, critical window of organ development in the ruminant relates to the period covering uterine attachment, or implantation, and rapid placental growth. During this period, there is pronounced cell division within developing organelles in many fetal tissues, leading to their structural development. In sheep, a 50% global reduction in caloric intake over this specific period profoundly affects placental growth and morphology, resulting in reduced placentome weight. This occurs in conjunction with a lower capacity to inactivate maternal cortisol through the enzyme 11β-hydroxysteroid dehydrogenase type 2 in response to a decrease in maternal plasma cortisol in early gestation. The birth weight of the offspring is, however, unaffected by this dietary manipulation and, although they possess more fat, this adaptation does not persist into adulthood when they become equally obese as those born to control fed mothers. Subsequently, after birth, further changes in fat development occur which impact on both glucocorticoid action and inflammatory responses. These adaptations can include changes in the relative populations of both brown and white adipocytes for which prolactin acting through its receptor appears to have a prominent role. Earlier when in utero nutrient restricted (i.e. between early-to-mid gestation) offspring are exposed to an obesogenic postnatal environment; they exhibit an exaggerated insulin response, which is accompanied by a range of amplified and thus, adverse, physiological or metabolic responses to obesity. These types of adaptations are in marked contrast to the effect of late gestational nutrient restriction, which results in reduced fat mass at birth. As young adults, however, fat mass is increased and, although basal insulin is unaffected, these offspring are insulin resistant. In conclusion, changes in nutrient supply to either the mother and/or her fetus can have profound effects on a range of metabolically important tissues. These have the potential to either exacerbate, or protect from, the adverse effects of later obesity and accompanying complications in the resulting offspring.     

Responses to cafeteria feeding in mice after the removal of interscapular brown adipose tissue

Feeding acafeteria diet to mice resulted in an increased energy intake of approximately 30% and this led to increases in the wet weight, total protein content , and total cytochrome oxidase activity of interscapular and dorso-cervical brown adipose tissue. Surgical removal of interscapular brown adipose tissue, followed by cafeteria feeding, gave rise to an elevation in dorso-cervical brown adipose tissue wet weight, total protein content, and total cytochrome oxidase activity, compared to intact cafeteria-fed mice. Cafeteria feeding with or without the removal of interscapular brown adipose tissue did not lead to significant increases in body weight compared to stock-fed control mice, but both cafeteria-fed groups of mice showed significant elevations in body fat content indicating that the induced hyperphagia led to a relative obesity in the cafeteria-fed groups. The results presented are consistent with an increased thermogenic activity in the brown adipose tissue of cafeteria-fed mice, and the effect of the removal of interscapular brown adipose tissue further indicates the quantitative importance of the tissue in the control of body weight.     

Ontogenetical changes in adipose tissue of the cat: Convertible adipose tissue

The ultrastructural characteristics of the inguinal, interscapular, and perirenal adipose tissue in kittens and cats were studied. There were no qualitative differences among adipocytes in the three anatomical areas. The only recorded difference was in the amount of lipids stored in the adipocytes in younger stages. Immediately after birth lipids occupied 25% of the volume in the inguinal area, 15% in interscapular fat tissue, and 10% in perirenal fat tissue. At this stage the adipose tissue morphologically resembled brown adipose tissue (BAT) of rodents. Two weeks after birth, lipids accumulated and adipocytes in the inguinal area became unilocular and appeared similar to white adipose tissue (WAT). A similar transition occurred approx 25 days after birth in interscapular fat and approx 6 weeks after birth in the perirenal area. No morphological signs of any cell degradation or destruction, nor any increased activity of preadipocytes, were seen during this conversion from BAT-like to WAT-like adipose tissue. The conversion of the adipose tissue was correlated with a decrease in vascularization and innervation, a loss of intercellular connections, and a changed mitochondrial population. Mitochondria in multilocular adipocytes resembled those in typical BAT which contain uncoupling protein (“UC-mitochondria”). After conversion to unilocular adipocytes the amount of mitochondria was halved, their cristae even more reduced, and their appearance was of a WAT-type (UCP-lacking mitochondria, which are coupled under physiological conditions; “C-mitochondria”). Since this category of adipose tissue differs from both typical brown and white adipose tissue, the name “convertible adipose tissue” (CAT) is proposed. Apparently adipose tissue from comparatively large mammals is of this convertible type.     

Effects of maternal nutrient restriction during early or mid-gestation without realimentation on maternal physiology and foetal growth and development in beef cattle

The aim of this study is to determine the effects of early and mid-gestation nutrient restriction on maternal metabolites and foetal growth. Primiparous Angus cows were synchronized and inseminated with semen from one sire. Dietary treatments were: control to gain 1 kg/week (CON) or 0.55% maintenance energy and CP requirements (nutrient restricted; NR). A subset of dams was fed NR (n=8) or CON (n=8) from days 30 to 110 of gestation. Another group was fed CON (n=8), days 30 to 190; NR (n=7), days 30 to 110 followed by CON days 110 to 190; or CON, (n=7) days 30 to 110 followed by NR days 110 to 190. Cows were harvested at days 110 or 190 of gestation, when foetal measurements and samples were collected. Cows that were NR during days 30 to 110 or 110 to 190 of gestation lost significant BW and body condition score (P<0.001), this was associated with reduced plasma glucose during NR (P<0.002). Foetal weights, empty foetal weights, abdominal and thoracic circumferences were all reduced (P<0.03) in day 110 NR animals. Foetal perirenal adipose as a percentage of empty foetal weight was increased (P=0.01) in NR day 110 female foetuses compared with CON foetus. Maternal serum triglycerides at day 110 of gestation were decreased (P<0.05) in NR dams, whereas foetal serum triglycerides were increased (P<0.05) in response to maternal NR. Foetal weights tended to be reduced (P=0.08) in NR/CON and CON/NR v. CON/CON cattle at day 190 of gestation. Empty foetal weights, abdominal and thoracic circumferences were reduced (P⩽0.03) in NR/CON and CON/NR v. CON/CON cattle. Brain weight as a percentage of empty foetal weight was increased (P<0.001) in NR/CON and CON/NR v. CON/CON cattle. Foetal perirenal adipose as a percentage of empty foetal weight was increased (P=0.003) in NR/CON and CON/NR v. CON/CON cattle. Maternal serum triglycerides at day 190 of gestation were decreased (P<0.05) in association with maternal NR. Foetal serum triglycerides at day 190 of gestation were increased (P<0.05) in response to maternal NR during early gestation but decreased by NR in mid gestation compared with CON foetuses. The data show that maternal nutrient restriction during early or mid-gestation cause’s asymmetrical foetal growth restriction, regardless if the restriction is preceded or followed by a period of non-restriction.     

Acute ethanol exposure in pregnancy alters the insulin-like growth factor axis of fetal and maternal sheep

Maternal ethanol intake during pregnancy impairs fetal growth, but mechanisms are not clearly defined. Reduced IGF abundance or bioavailability in the fetus and/or mother may contribute to this growth restriction. We hypothesized that an episode of acute ethanol exposure, mimicking binge drinking would restrict fetal growth and perturb the maternal and fetal IGF axes. Pregnant sheep were infused intravenously with saline or ethanol (1 g/kg maternal wt) over 1 h, on days 116, 117, and 118 of gestation (start of 1st infusion = time 0, term is 147 days). Maternal and fetal plasma IGF and IGF-binding protein (IGFBP) concentrations were measured before and after each infusion. Compared with controls, ethanol exposure reduced fetal weight at day 120 by 19%, transiently reduced maternal plasma IGF-I (-35%) at 30 h, and decreased fetal plasma IGF-II (-28%) from 24 to 54 h after the first infusion. Ethanol exposure did not alter maternal or fetal plasma concentrations of IGFBP-2 and IGFBP-3, measured by Western ligand blotting. We conclude that suppression of maternal and fetal IGF abundance may contribute to fetal growth restriction induced by acute or binge ethanol exposure.     

Ontogeny and nutritional programming of adiposity in sheep: potential role of glucocorticoid action and uncoupling protein-2

Increased glucocorticoid action and adipose tissue inflammation contribute to excess adiposity. These adaptations may be enhanced in offspring exposed to nutrient restriction (NR) in utero, thereby increasing their susceptibility to later obesity. We therefore determined the developmental ontogeny of glucocorticoid receptor (GR), 11beta-hydroxysteroid dehydrogenase (11betaHSD) types 1 and 2, and uncoupling protein (UCP)-2 mRNA in perirenal adipose tissue between late gestation and 6 mo after birth in the sheep, as well as the effect of maternal NR targeted between early to mid (28-80 days, term approximately 147 days)- or late (110-147 days) gestation. GR and 11betaHSD1 mRNA increased with fat mass and were all maximal within the 6-mo observation period. 11betaHSD2 mRNA abundance demonstrated a converse decline, whereas UCP2 peaked at 30 days. GR and 11betaHSD1 mRNA abundance were strongly correlated with total and relative perirenal adipose tissue weight, and UCP2 was strongly correlated with GR and 11betaHSD1 mRNA. Early- to midgestational NR increased GR, 11betaHSD1, and UCP2 mRNA, but decreased 11betaHSD2 mRNA abundance, an adaptation reversed with late-gestational NR. We conclude that the continual rise in glucocorticoid action and fat mass after birth may underlie the development of later obesity. The magnitude of this adaptation is partly dependent on maternal food intake through pregnancy.     

Maternal high-fat diet programming of the neuroendocrine system and behavior

This article is part of a Special Issue “SBN 2014”.Maternal obesity, metabolic state, and diet during gestation have profound effects on offspring development. The prevalence of neurodevelopmental and mental health disorders has risen rapidly in the last several decades in parallel with the rise in obesity rates. Evidence from epidemiological studies indicates that maternal obesity and metabolic complications increase the risk of offspring developing behavioral disorders such as attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASD), and schizophrenia. Animal models show that a maternal diet high in fat similarly disrupts behavioral programming of offspring, with animals showing social impairments, increased anxiety and depressive behaviors, reduced cognitive development, and hyperactivity. Maternal obesity, metabolic conditions, and high fat diet consumption increase maternal leptin, insulin, glucose, triglycerides, and inflammatory cytokines. This leads to increased risk of placental dysfunction, and altered fetal neuroendocrine development. Changes in brain development that likely contribute to the increased risk of behavioral and mental health disorders include increased inflammation in the brain, as well as alterations in the serotonergic system, dopaminergic system and hypothalamic–pituitary–adrenal (HPA) axis.     

Maternal obesity at conception programs obesity in the offspring

Risk of obesity in adult life is subject to programming during gestation. To examine whether in utero exposure to maternal obesity increases the risk of obesity in offspring, we developed an overfeeding-based model of maternal obesity in rats utilizing intragastric feeding of diets via total enteral nutrition. Feeding liquid diets to adult female rats at 220 kcal/kg(3/4) per day (15% excess calories/day) compared with 187 kcal/kg(3/4) per day for 3 wk caused substantial increase in body weight gain, adiposity, serum insulin, leptin, and insulin resistance. Lean or obese female rats were mated with ad libitum AIN-93G-fed male rats. Exposure to obesity was ensured to be limited only to the maternal in utero environment by cross-fostering pups to lean dams having ad libitum access to AIN-93G diets throughout lactation. Numbers of pups, birth weight, and size were not affected by maternal obesity. Male offspring from each group were weaned at postnatal day (PND)21 to either AIN-93G diets or high-fat diets (45% fat calories). Body weights of offspring from obese dams did not differ from offspring of lean dams when fed AIN-93G diets through PND130. However, offspring from obese dams gained remarkably greater (P < 0.005) body weight and higher % body fat when fed a high-fat diet. Body composition was assessed by NMR, X-ray computerized tomography, and weights of adipose tissues. Adipose histomorphometry, insulin sensitivity, and food intake were also assessed in the offspring. Our data suggest that maternal obesity at conception leads to fetal programming of offspring, which could result in obesity in later life.     

Differential effects of maternal hypoxia or nutrient restriction on carotid and femoral vascular function in neonatal rats

In response to reduced oxygen or nutrient supply, the fetus may redistribute cardiac output to conserve brain and heart growth, at the expense of the peripheral tissues; however, it is not known whether alterations in vascular function are maintained after birth or whether reduced fetal oxygen versus nutrient supply produces distinct effects. Using a pressure myograph, we examined isolated carotid and femoral artery responses to phenylephrine and endothelin-1 in neonatal rats, after either reduced maternal oxygen or global nutrient restriction during late gestation. Timed-pregnant Sprague-Dawley rats were randomly assigned to control (n = 10), hypoxia (12% O2, n = 9), or nutrient restriction (NR, 40% of control diet, n = 7) protocol and treated from day 15-21 of pregnancy. Pups were collected 3-12 h after birth. Neonatal weights (P < 0.001) and relative liver weights (P < 0.001) were lower in hypoxia and nutrient restriction treatments compared with control, while relative heart weights were greater in the hypoxia than in the control or nutrient restriction groups (P < 0.01). Constriction to phenylephrine was reduced in carotid arteries from the hypoxia and nutrient restriction groups compared with control (P < 0.001), while the femoral artery response was greater in hypoxia-treated neonates compared with control or nutrient-restricted neonates (P < 0.01). Only the hypoxia reduced carotid responses to endothelin-1, while no differences were observed in the endothelin-1 responses in femoral arteries. Maternal hypoxia and maternal nutrient restriction produced distinct effects on heart growth and neonatal vascular function, suggesting that regional changes in cardiovascular function after poor fetal growth are dependent on the nature of the insult in utero.