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Small-for-gestational age (SGA) human newborns have an increased risk of hyperphagia and obesity, as well as a spectrum of neurologic and neurobehavioral abnormalities. We have shown that the SGA hypothalamic (appetite regulatory site) neuroprogenitor cells (NPCs) exhibit reduced proliferation and neuronal differentiation. DNA methylation (DNA methyltransferase; DNMT1) regulates neurogenesis by maintaining NPC proliferation and suppressing premature differentiation. Once differentiation ensues, DNMT1 preferentially promotes neuronal and inhibits astroglial fate. We hypothesized that the programmed dysfunction of NPC proliferation and differentiation in SGA offspring is epigenetically mediated via DNMT1. Pregnant rats received either ad libitum food (Control) or were 50% food-restricted to create SGA offspring. Primary hypothalamic NPCs from 1 day old SGA and Controls newborns were cultured and transfected with nonspecific or DNMT1-specific siRNA. NPC proliferation and protein expression of specific markers of NPC (nestin), neuroproliferative transcription factor (Hes1), neurons (Tuj1) and astrocytes (GFAP) were determined. Under basal conditions, SGA NPCs exhibited decreased DNMT1 and reduced proliferation and differentiation, as compared to Controls. In both SGA and Controls, DNMT1 siRNA in complete media inhibited NPC proliferation, consistent with reduced expression of nestin and Hes1. In differentiation media, DNMT1 siRNA decreased expression of Tuj1 but increased GFAP. In vivo data replicated these findings. In SGA offspring, impaired neurogenesis is epigenetically mediated, in part, via reduction in DNMT1 expression and suppression of Hes1 resulting in NPC differentiation. It is likely that the maturation of regions beyond the hypothalamus (e.g., cerebral cortex, hippocampus) may be impacted, contributing to poor cognitive and neurobehavioral competency in SGA offspring., (Copyright © 2019. Published by Elsevier Ltd.)

Intrauterine growth restriction (IUGR) with rapid catch-up growth leads to adult obesity and insulin resistance. We have previously shown that IUGR male rats demonstrated increased de novo fatty acid synthesis in the subcutaneous (SC) fat, but not the visceral fat, during the nursing period prior to the onset of obesity. Young IUGR females do not exhibit the same increase. We further hypothesized that in male IUGR offspring, de novo synthesis is a programmed intrinsic effect that persists to adulthood and does not suppress in response to a high fat diet. We measured fatty acid de novo synthesis in IUGR adult males (6 months) using deuterium-enriched drinking water as a stable isotope tracer, then further studied the response after consumption of an isocaloric high fat diet. Baseline de novo synthesis in adult females was also studied at age 9 months. Males demonstrated increased baseline de novo synthesis in both SC fat and visceral fat. Correspondingly, SC and visceral fat protein expression of lipogenic enzymes acetyl-coA carboxylase-α (ACCα) and fatty acid synthase were upregulated. After the isocaloric high fat diet, de novo synthesis was suppressed such that no differences remained between the two groups, although, IUGR SC fat demonstrated persistently increased lipogenic protein expression. In contrast, de novo synthesis among adult females is not impacted in IUGR. In conclusion, enhancement of male IUGR SC fat de novo synthesis appears to be an early consequence of metabolic programming, whereas enhancement in visceral fat appears to be a later consequence.

Intrauterine growth restriction (IUGR) is associated with altered food preferences, which may contribute to increased risk of obesity. We evaluated the effects of IUGR on attention to a palatable food cue, as well as tyrosine hydroxylase (TH) content in the orbitofrontal cortex (OFC) and nucleus accumbens (NAcc) in response to sweet food intake. From day 10 of gestation and through lactation, Sprague-Dawley rats received either an ad libitum (Adlib) or a 50% food-restricted (FR) diet. At birth, pups were cross-fostered, generating four groups (gestation/lactation): Adlib/Adlib (control), FR/Adlib (intrauterine growth-restricted), Adlib/FR, and FR/FR. Adult attention to palatable food cues was measured using the Attentional Set-Shifting Task (ASST), which uses a sweet pellet as reward. TH content in the OFC and NAcc was measured at baseline and in response to palatable food intake. At 90 days of age, FR/Adlib males ate more sweet food than controls, without differences in females. However, when compared to Controls, FR/Adlib females needed fewer trials to reach criterion in the ASST (p=0.04) and exhibited increased TH content in the OFC in response to sweet food (p=0.03). In the NAcc, there was a differential response of TH content after sweet food intake in both FR/Adlib males and females (p<0.05). Fetal programming of adult food preferences involves the central response to palatable food cues and intake, affecting dopamine release in select structures of the brain reward system., (Copyright © 2015 Elsevier B.V. All rights reserved.)

A newly recognized primary cause of the obesity epidemic is the developmental programming effects of infants born to mothers with obesity or gestational diabetes, intrauterine growth-restricted newborns, and offspring exposed to environmental toxins including bisphenol A. The mechanisms which result in offspring obesity include the programming of the hypothalamic appetite pathway and adipogenic signals regulating lipogenesis. Processes include nutrient sensors, epigenetic modifications, and alterations in stem cell precursors of both appetite/satiety neurons and adipocytes which are modulated to potentiate offspring obesity. Future strategies for the prevention and therapy of obesity must address programming effects of the early life environment.

Objective: We hypothesized that gestationally programmed nonalcoholic fatty liver disease in low-birthweight offspring is mediated through nutrient sensors nicotinamide adenine dinucleotide+-dependent histone deacetylase (SIRT1) and AMP-activated protein kinase (AMPK)., Study Design: Pregnant dams received ad libitum food or were 50% food restricted from pregnancy days 10-21 to produce control and low-birthweight newborn offspring, respectively. All pups were nursed by control dams and weaned to ad libitum feed. We determined hepatic SIRT1 and AMPK activities and protein expression of lipid targets in low-birthweight and control fetuses, newborns, and adult offspring (3 months)., Results: Low-birthweight fetuses demonstrated increased prenatal hepatic SIRT1 activity, although with increased lipogenesis. After birth, low-birthweight newborn offspring undergo postnatal suppression of hepatic SIRT1 and AMPK activities in conjunction with increased lipogenesis, decreased lipolysis, and increased fat stores., Conclusion: These findings suggest that undernutrition stress in utero may program hepatic nutrient sensors to perceive normal postnatal nutrition as a state of nutrient excess with the induction of hepatic lipid storage., (Copyright © 2012 Mosby, Inc. All rights reserved.)

We have shown that intrauterine fetal growth restriction (IUGR) newborn rats exhibit hyperphagia, reduced satiety, and adult obesity. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a principal metabolic regulator that specifically regulates appetite in the hypothalamic arcuate nucleus (ARC). In response to fasting, upregulated AMPK activity increases the expression of orexigenic (neuropeptide Y [NPY] and agouti-related protein [AgRP]) and decreases anorexigenic (proopiomelanocortin [POMC]) peptides. We hypothesized that IUGR offspring would exhibit upregulated hypothalamic AMPK, contributing to hyperphagia and obesity. We determined AMPK activity and appetite-modulating peptides (NPY and POMC) during fasting and fed conditions in the ARC of adult IUGR and control females. Pregnant rats were fed ad libitum diet (control) or were 50% food restricted from gestation day 10 to 21 to produce IUGR newborns. At 10 months of age, hypothalamic ARC was dissected from fasted (48 hours) and fed control and IUGR females. Arcuate nucleus messenger RNA ([mRNA] NPY, AgRP, and POMC) and protein expression (total and phosphorylated AMPK, Akt) was determined by quantitative reverse transcriptase-polymerase chain reaction and Western Blot, respectively. In the fed state, IUGR adult females demonstrated evidence of persistent appetite stimulation with significantly upregulated phospho (Thr(172))-AMPKα/AMPK (1.3-fold), NPY/AgRP (2.3/1.8-fold) and decreased pAkt/Akt (0.6-fold) and POMC (0.7-fold) as compared to fed controls. In controls though not IUGR adult females, fasting significantly increased pAMPK/AMPK, NPY, and AgRP and decreased pAkt/Akt and POMC. Despite obesity, fed IUGR adult females exhibit upregulated AMPK activity and appetite stimulatory factors, similar to that exhibited by fasting controls. These results suggest that an enhanced appetite drive in both fed and fasting states contributes to hyperphagia and obesity in IUGR offspring.

Intrauterine growth-restricted (IUGR) newborns have increased risk of adult metabolic syndrome, including fatty liver. However, it is unclear whether the fatty liver development is "programmed" or secondary to the accompanying obesity. In this study, we examined hepatic lipid accumulation and lipid-regulatory factors (sterol regulatory element-binding protein-1c and fatty acid synthase) in IUGR and Control fetal (embryonic day 20; e20) and newborn (postnatal day 1; p1) rat pups. Notably, despite of in utero undernutrition state, IUGR fetuses demonstrated "fatty liver" with upregulation of these lipogenic indices at as early as e20. Both IUGR and Control newborns exhibited the same extent of massive increase in hepatic lipid content, whereas IUGR newborns continued to exhibit upregulated lipogenic indices. The persistent upregulation of the lipogenic indices in fetal and newborn IUGR suggests that fatty liver is gestationally programmed. Our study suggested that IUGR offspring were born with an altered metabolic life strategy of increased fuel/lipid storage which could be a distinct metabolic pathway of the thrifty phenotype., (© 2011 The Authors. Congenital Anomalies © 2011 Japanese Teratology Society.)

Maternal undernutrition (MUN) during pregnancy may lead to fetal intrauterine growth restriction (IUGR), which itself predisposes to adult risk of obesity, hypertension, and diabetes. IUGR may stem from insufficient maternal nutrient supply or reduced placental nutrient transfer. In addition, a critical role for maternal stress-induced glucocorticoids (GCs) has been suggested to contribute to both IUGR and the ensuing risk of adult metabolic syndrome. While GC-induced fetal organ defects have been examined, there have been few studies on placental responses to MUN-induced maternal stress. Therefore, we hypothesize that 50% MUN associates with increased maternal GC levels and decreased placental HSD11B. This in turn leads to decreased placental and fetal growth, hence the need to investigate nutrient transporters. We measured maternal serum levels of corticosterone, and the placental basal and labyrinth zone expression of glucocorticoid receptor (NR3C1), 11-hydroxysteroid dehydrogenase B 1 (HSD11B-1) predominantly activates cortisone to cortisol and 11-dehydrocorticosterone (11-DHC) to corticosterone, although can sometimes drive the opposing (inactivating reaction), and HSD11B-2 (only inactivates and converts corticosterone to 11-DHC in rodents) in control and MUN rats at embryonic day 20 (E20). Moreover, we evaluated the expression of nutrient transporters for glucose (SLC2A1, SLC2A3) and amino acids (SLC38A1, 2, and 4). Our results show that MUN dams displayed significantly increased plasma corticosterone levels compared to control dams. Further, a reduction in fetal and placental weights was observed in both the mid-horn and proximal-horn positions. Notably, the placental labyrinth zone, the site of feto-maternal exchange, showed decreased expression of HSD11B1-2 in both horns, and increased HSD11B-1 in proximal-horn placentas, but no change in NR3C1. The reduced placental GCs catabolic capacity was accompanied by downregulation of SLC2A3, SLC38A1, and SLC38A2 expression, and by increased SLC38A4 expression, in labyrinth zones from the mid- and proximal-horns. In marked contrast to the labyrinth zone, the basal zone, which is the site of hormone production, did not show significant changes in any of these enzymes or transporters. These results suggest that dysregulation of the labyrinth zone GC "barrier", and more importantly decreased nutrient supply resulting from downregulation of some of the amino acid system A transporters, may contribute to suboptimal fetal growth under MUN.

A newly recognized primary cause of obesity epidemic is the developmental programming effects of (1) intrauterine growth-restricted (IUGR) newborns exposed in utero to undernutrition, and (2) normal or excessive weight newborns exposed to maternal obesity and high-fat (HF) diets. The mechanisms contributing to offspring obesity have been extensively studied in animal models with adipose tissue identified as one of the principal targets of programming. IUGR and HF offspring exhibit programmed adipocytes, such that an intrinsic enhanced lipogenesis and adipocyte proliferation contribute to the development of obesity. This is attributed to early induction of adipogenic transcription factor peroxisome proliferator-activated receptor (PPAR)γ, whose activity is enhanced under limited or excess nutrient availability. Nonetheless, this occurs via different mechanisms involving PPARγ coregulators: In IUGR, it is upregulation of coactivators, whereas in HF newborns, it is downregulation of corepressors. Thus preventive therapeutic interventions will require target-specific modalities that depend on the primary etiology., (© Thieme Medical Publishers.)

Maternal food restriction (FR) during pregnancy results in intrauterine growth-restricted (IUGR) offspring that show rapid catch-up growth and develop metabolic syndrome and adult obesity. However, continued nutrient restriction during nursing delays catch-up growth and prevents development of obesity. Epigenetic regulation of IGF1, which modulates growth and is synthesized and secreted by the liver, may play a role in the development of these morbidities. Control (AdLib) pregnant rats received ad libitum food through gestation and lactation, and FR dams were exposed to 50% food restriction from days 10 to 21. FR pups were nursed by either ad libitum-fed control dams (FR/AdLib) or FR dams (FR/FR). All pups were weaned to ad libitum feed. Maternal FR resulted in IUGR newborns with significantly lower liver weight and, with the use of chromatin immunoprecipitation, decreased dimethylation at H3K4 in the IGF1 region was observed. Obese adult FR/AdLib males had decreased dimethylation and increased trimethylation of H3K4 in the IGF1 region. This corresponded to an increase in mRNA expression of IGF1-A (134 ± 5%), IGF1-B (165 ± 6%), IGF1 exon 1 (149 ± 6%), and IGF1 exon 2 (146 ± 7%) in the FR/AdLib compared with the AdLib/AdLib control group. In contrast, nonobese FR/FR had significantly higher IGF1-B mRNA levels (147 ± 19%) than controls with no difference in IGF1-A, exon 1 or exon 2. Modulation of the rate of IUGR newborn catch-up growth may thus protect against IGF1 epigenetic modifications and, consequently, obesity and associated metabolic abnormalities.

Uteroplacental insufficiency (UPI) induced intrauterine growth restriction (IUGR) predisposes individuals to adult onset metabolic morbidities, including insulin resistance and cardiovascular disease. An underlying component of the development of these morbidities is adipose dysfunction; specifically a disproportionately abundant visceral adipose tissue. We hypothesize that IUGR will increase rats visceral adiposity and visceral expression of PPARgamma, a key regulator of adipogenesis. To test this hypothesis we employed a well described UPI induced IUGR rat model. Subcutaneous and visceral adipose levels were measured in adolescent control and IUGR rats using MRI. Expression of PPARgamma mRNA and protein, as well as PPARgamma target genes, was measured in neonatal, adolescent and adult rats. UPI induced IUGR increases the relative amount of visceral adipose tissue in male, but not female, adolescent rats in conjunction with an increase in PPARgamma2mRNA and protein in male visceral adipose. Importantly, these effects are seen prior to the onset of overt obesity. We conclude that increased PPARgamma2 expression in VAT of IUGR males is associated with increased visceral adiposity. We speculate that the increase in visceral adiposity may contribute to the metabolic morbidities experienced by this population., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)

Although "fetal programming" has been extensively studied in many organs, there is only limited information on pulmonary effects in the offspring following intrauterine growth restriction (IUGR). We aimed to determine the effects of nutrient restriction on the lung structure and lung lipid differentiation programs in offspring using an animal mode of maternal food restriction (MFR). We utilized a rodent model of 50% MFR from day 10 of gestation to term and then using lung morphology, Western blotting, Real Time RT-PCR and Oil Red O staining, lung structure and development of the offspring were examined at postnatal days (p) 1, p21, and 9 months (9M). At postnatal day 1, MFR pups weighed significantly less compared to control pups, but at p21 and 9M, they weighed significantly more. However, lung weight, expressed as a percentage of body weight between the two groups was not different at all time-points examined. The MFR group had significantly decreased alveolar number and significantly increased septal thickness at p1 and 9M, indicating significantly altered lung structure in the MFR offspring. Furthermore, although at p1, compared to the control group, lung lipid accumulation was significantly decreased in the MFR group, at 9M, it was significantly increased. There were significant temporal changes in the parathyroid hormone-related protein/peroxisome proliferator-activated receptor gamma signaling pathway and surfactant synthesis. We conclude that MFR alters fetal lung lipid differentiation programming and lung morphometry by affecting specific epithelial-mesenchymal signaling pathways, offering the possibility for specific interventions to overcome these effects.

As enhanced adipogenesis contributes to programmed obesity, adipogenic and lipogenic signaling pathways in intrauterine growth restricted (IUGR) offspring were examined. From 10 days to term gestation, rats received ad libitum food (control) or were 50% food-restricted (IUGR). Pups were nursed and weaned to ad libitum diet. mRNA and protein levels of adipogenic transcription factors and lipid enzymes (1 day and 9 month) and adipocyte cell size (3 weeks and 9 months) were determined. One day-old IUGR males showed upregulation of peroxisome proliferator-activated receptor (PPAR gamma(2)), including upstream factors regulating PPAR gamma, and RXR alpha, with which PPAR gamma heterodimerizes. Intracellular lipolytic enzyme (hormone-sensitive lipase) was downregulated. Nine-month-old IUGR males showed upregulation of adipogenic and lipogenic (SREBP1c) transcription factors with upregulation of enzymes facilitating fatty acid uptake (lipoprotein lipase) and synthesis (fatty acid synthase), leading to hypertrophic adipocytes. Paradoxical upregulation of adipogenesis signaling cascade prior to the development of obesity in IUGR males suggests early changes in signaling mechanisms.

Objective: Intrauterine growth-restricted (IUGR) newborns have increased risk of obesity-induced fatty liver and inflammation. We hypothesized that IUGR-induced inhibition of hepatic peroxisome proliferator-activated receptors (PPARs) is associated with an increased inflammatory response., Study Design: Rat control dams received ad libitum food, whereas study dams were 50% food restricted from pregnancy day 10 to 21 (IUGR). Pups were nursed by control dams and weaned to ad libitum feed. Hepatic protein expression of transcription factors, lipid enzymes, triglyceride content, and C-reactive protein (CRP) levels were analyzed in 1 day and 9 month old male offspring., Results: At 1 day of age, IUGR pups showed down-regulation of PPARalpha and PPARgamma and up-regulation of hepatic lipase and CRP. At 9 months of age, IUGR exhibited continued down-regulation of PPARalpha and PPARgamma with up-regulation of sterol regulatory element-binding protein-1 and fatty acid synthase. Furthermore, IUGR adults had increased hepatic triglyceride content and plasma CRP levels., Conclusions: The results suggest that developmental hepatic dysregulation may contribute to programmed obesity-induced inflammation in IUGR offspring.

Fetal growth restriction (FGR) has been associated with an increased incidence of cardiovascular disease in adult life. Animal models of restricted fetal growth often cause FGR over discrete periods of gestation and hence may not be applicable to individuals with low birthweight but who are not clinically growth-restricted. Our aim was to determine whether spontaneously occurring differences in fetal growth influence the functional development of the hypothalamic-pituitary-adrenal (HPA) axis or the renin-angiotensin system (RAS), both of which are involved in arterial pressure regulation. Using sheep, arterial pressure and heart rate were monitored in chronically catheterised singleton and twin fetuses at 130, 134 and 137 days of gestation (term approximately 147 days). Fetuses were challenged, at different times, with exogenous angiotensin (Ang) II, combined administration of arginine vasopressin and corticotrophin releasing hormone (AVP+CRH) and adrenocorticotrophic hormone (ACTH); fetal cardiovascular responses and circulating cortisol concentrations were measured. In all fetuses Ang II and AVP+CRH altered cardiovascular function (increase in mean arterial pressure and decrease in heart rate); both AVP+CRH and ACTH increased circulating cortisol concentrations. Responses were not related to fetal bodyweight. We conclude that naturally occurring differences in growth do not influence the development of the HPA axis or RAS function in fetal sheep.

Objective: Modulation of growth of intrauterine growth restricted (IUGR) newborns causes either adult obesity or normalization of body weight and fat. We investigated the impact of rapid versus delayed catch-up growth of IUGR offspring on glucose and lipid profiles., Study Design: From 10 days to term gestation and through lactation, control pregnant rats received ad libitum food, whereas study rats were 50% food restricted. Cross-fostering techniques were used to examine effects of food restriction during pregnancy and/or lactation periods. Glucose and lipid profiles were determined in offspring at ages 1 day, 3 weeks, and 9 months., Results: Food restriction during pregnancy produced hypoglycemic IUGR pups. Those permitted rapid catch-up growth demonstrated adult obesity with insulin resistance (hyperglycemia/hyperinsulinemia) and hypertriglyceridemia. Conversely, IUGR exhibiting delayed catch-up growth demonstrated normal adult body weight and insulin deficiency (hyperglycemia/hypoinsulinemia) and elevated cholesterol levels as compared with controls. However, these adult offspring had higher glucose though similar insulin levels as control offspring nursed by food restricted dam., Conclusion: The timing and the rate of IUGR newborn catch-up growth causes markedly altered adult phenotypes. Although delayed newborn catch-up growth may be beneficial in the prevention of adult obesity, there may be significant adverse effects on pancreatic function.

Maternal food restriction during pregnancy results in intrauterine growth-restricted (IUGR) newborns with significantly decreased plasma leptin levels. When nursed by ad libitum-fed controls, IUGR offspring exhibit hyperphagia with adult obesity, marked by increased percentage body fat and plasma leptin, suggesting altered anorexigenic pathways. The authors examined leptin signaling pathways and food intake responses to 2 putative anorexic effectors (leptin and sibutramine, a serotonin reuptake inhibitor) in IUGR offspring. From 10 days to term gestation and through lactation, control pregnant rats received ad libitum food, whereas study rats were 50% food restricted. Following birth, litter size was standardized, and all offspring were nursed by control dams. At 3 weeks of age, offspring were weaned to ad libitum laboratory chow. At ages 1 day and 3 weeks, hypothalamic leptin receptor (Ob-Rb) mRNA and total STAT3 protein expression were determined. In addition, phosphorylated STAT3 was measured in 1-day-old offspring administered peripheral leptin. In prepubescent and adult offspring, anorexic effects of leptin and sibutramine were determined. At 1 day of age, IUGR pups showed increased hypothalamic Ob-Rb mRNA and total STAT3 protein expression though reduced leptin activated phosphorylated STAT3. At 3 weeks of age, IUGR offspring had decreased hypothalamic Ob-Rb mRNA expression, although with continued elevated STAT3 protein levels. The IUGR offspring demonstrated resistance to anorexigenic agents, leptin (6 weeks and 6 months), and sibutramine (8 months), as evidenced by less reduction in food intake and less body weight loss than controls. The IUGR offspring demonstrate suppressed leptin-induced STAT3 phosphorylation and impaired anorexigenic response to 2 factors in the central satiety pathway. This reduced anorexigenic function, together with normal or perhaps enhanced orexigenic function, contributes to the development of programmed obesity in IUGR rat offspring.

Objective: Intrauterine growth restriction demonstrates increased risk of adult metabolic syndrome. The associated hyperlipidemia results from obesity or programmed metabolic abnormalities. Because lipid homeostasis is regulated by the liver, we hypothesized that hepatic structure and lipid content in intrauterine growth restriction would reflect a primary lipid dysfunction., Study Design: From 10 days to term gestation, control pregnant rats received ad libitum diet; study rats were 25% food-restricted (FR). All dams received ad libitum diet throughout lactation. At 3 weeks of age, hepatic lobule size and lipid profile of the pups were determined., Results: At 3 weeks of age, body and liver weights of the pups were comparable with controls, although with reduced hepatic lobule size. FR males had increased hepatic triglyceride and cholesterol content with elevated sterol regulatory element-binding protein-1c, fatty acid synthase, and lipoprotein lipase expression; FR females exhibited decreased hepatic cholesterol levels. Plasma lipid levels were unchanged in FR males and females., Conclusion: Developmental programming results in sex-dependent altered lipid metabolism with increased risk in males.

Objective: An increased risk of adult hypertension, obesity, and coronary heart disease occurs in low birth weight or intrauterine growth-restricted newborn infants as a result of fetal programming. Human twins represent a natural model of low birth weight and intrauterine growth restriction because they are significantly smaller at birth than singleton infants because of both earlier delivery and reduced intrauterine growth. Increased blood pressure has been reported in several epidemiologic studies of human twin offspring, although this has not been confirmed in an animal model. Because the sheep pregnancy consists of singleton and twin litters, we sought to determine the impact of ovine twin gestation and twin nursing on the cardiovascular and renal function of the offspring., Study Design: Newborn lambs (n = 12) were studied at 21 +/- 2 day of life. Both singleton (n = 6) and twin lambs (n = 6) were born to ewes provided ad libitum water and food throughout gestation. After the delivery, ewes were provided ad libitum water and food, and newborn lambs were allowed ad libitum nursing with the maternal ewe. At 15 +/- 2 days of age, the lambs were prepared with vascular and renal catheters and studied at 21 +/- 2 days. After a 2-hour basal period, lambs received an intravenous infusion of hypotonic (0.075 mol/L) NaCl (0.15 ml/kg/hr) for an additional 2 hours. Newborn arterial blood pressure, heart rate, and urine flow were monitored continuously, and arterial blood samples were obtained before, during, and after the infusion., Results: At birth, twin lambs weighed 30% less than singleton lambs (3.5 +/- 0.1 kg vs 5.0 +/- 0.2 kg; P < .05), although 50% less at 21 days (5.2 +/- 0.6 vs 10.8 +/- 1.2 kg). There were marked differences in basal arterial blood values between twin and singleton lambs at 21 days, with twins having significantly increased plasma sodium and systolic, diastolic, and mean arterial pressures and reduced glomerular filtration rates, urine osmolality, osmolar excretion, and osmolar clearance (per kg body weight) compared with singleton lambs. In response to hypotonic saline solution infusion, the plasma composition and blood pressure differences between twin and singleton lambs persisted., Conclusion: These results indicate that ovine twin gestation and nursing markedly reduced body weight at 21 days of age, with evidence of plasma hypernatremia, hypertension, and reduced glomerular filtration rates, which persisted throughout hypotonic saline solution infusion. Consistent with epidemiologic studies of humans, these results demonstrate that gestational/newborn nutrient stress may program hypertension in offspring.

The degree of nutrient enhancement during the newborn period may modulate programming of appetite-regulating hormones, body composition, and propensity to adult obesity in intrauterine growth-restricted (IUGR) newborns. Pregnant rats received, from day 10 to term gestation and throughout lactation, ad libitum food (AdLib) or 50% food restriction (FR) to produce IUGR newborns. AdLib vs. FR offspring were studied at day 1, and, to create two distinct groups of newborn catch-up growth (immediate, delayed) among the IUGR newborns, cross-fostering techniques were employed. The four groups of pups at 3 wk were IUGR immediate catch-up growth (FR/AdLib), IUGR delayed catch-up growth (FR/FR), control (AdLib/AdLib), and lactation FR control (AdLib/FR). From 3 wk to 9 mo, all offspring had AdLib rat chow. Maternal FR during pregnancy resulted in IUGR pups (6.0 +/- 0.3 vs. 7.1 +/- 0.3 g, P < 0.01) with decreased leptin (0.66 +/- 0.03 vs. 1.63 +/- 0.12 ng/ml, P < 0.001) and increased ghrelin (0.43 +/- 0.03 vs. 0.26 +/- 0.02 ng/ml, P < 0.001). Maternal FR during lactation (FR/FR) further impaired IUGR offspring growth at 3 wk. However, by 9 mo, these pups attained normal body weight, percent body fat, and plasma leptin levels. Conversely, IUGR offspring nursed by AdLib dams (FR/AdLib) exhibited rapid catch-up growth at 3 wk and continued accelerated growth, resulting in increased weight, percent body fat, and plasma leptin levels. Thus the degree of newborn nutrient enhancement and timing of IUGR newborn catch-up growth may determine the programming of orexigenic hormones and offspring obesity.

Small-for-gestational age (SGA) human newborns have an increased risk of hyperphagia and obesity, as well as a spectrum of neurologic and neurobehavioral abnormalities. We have shown that the SGA hypothalamic (appetite regulatory site) neuroprogenitor cells (NPCs) exhibit reduced proliferation and neuronal differentiation. DNA methylation (DNA methyltransferase; DNMT1) regulates neurogenesis by maintaining NPC proliferation and suppressing premature differentiation. Once differentiation ensues, DNMT1 preferentially promotes neuronal and inhibits astroglial fate. We hypothesized that the programmed dysfunction of NPC proliferation and differentiation in SGA offspring is epigenetically mediated via DNMT1. Pregnant rats received either ad libitum food (Control) or were 50% food-restricted to create SGA offspring. Primary hypothalamic NPCs from 1 day old SGA and Controls newborns were cultured and transfected with nonspecific or DNMT1-specific siRNA. NPC proliferation and protein expression of specific markers of NPC (nestin), neuroproliferative transcription factor (Hes1), neurons (Tuj1) and astrocytes (GFAP) were determined. Under basal conditions, SGA NPCs exhibited decreased DNMT1 and reduced proliferation and differentiation, as compared to Controls. In both SGA and Controls, DNMT1 siRNA in complete media inhibited NPC proliferation, consistent with reduced expression of nestin and Hes1. In differentiation media, DNMT1 siRNA decreased expression of Tuj1 but increased GFAP. In vivo data replicated these findings. In SGA offspring, impaired neurogenesis is epigenetically mediated, in part, via reduction in DNMT1 expression and suppression of Hes1 resulting in NPC differentiation. It is likely that the maturation of regions beyond the hypothalamus (e.g., cerebral cortex, hippocampus) may be impacted, contributing to poor cognitive and neurobehavioral competency in SGA offspring.

Intrauterine growth restricted (IUGR) offspring exhibit increased appetite and a propensity to adult obesity. Although the rate of newborn catch-up growth may determine the programming of adult obesity, there is little understanding of mechanisms by which orexigenic pathways are modified. Ghrelin is an orexigenic peptide that acts in the hypothalamic arcuate (ARC) and ventromedial (VMH) nuclei. To examine potential programming effects of IUGR, ghrelin's actions on ARC and VMH neurons were studied in brain slices of adult offspring previously subjected to maternal food restriction (FR) during pregnancy (FR/AdLib [ad libitum]) and both pregnancy and lactation (FR/FR). FR/FR offspring demonstrated increased baseline neuronal firing frequency in both ARC and VMH when compared with both FR/AdLib and control offspring. Among FR/AdLib pups that exhibit hyperphagia and obesity, ghrelin excited more and inhibited fewer ARC neurons when compared with either FR/FR or controls. These results provide evidence of programming of orexigenic/anorexigenic mechanisms depending on the nutrient levels during pregnancy and newborn periods. [ABSTRACT FROM AUTHOR]

Objective: Maternal food restriction during pregnancy results in growth-restricted newborns and reduced glomerular number, contributing to programmed offspring hypertension. We investigated whether reduced nephrogenesis may be programmed by dysregulation of factors controlling ureteric bud branching and mesenchyme to epithelial transformation. Study Design: At 10 to 20 days'' gestation, Sprague Dawley pregnant rats (n = 6/group) received ad libitum food; food-restricted rats were 50% food restricted. At embryonic day 20, messenger ribonucleic acid (mRNA) and protein expression of Wilms'' tumor 1 gene product (WT1), paired box transcription factor (Pax)-2, fibroblast growth factor (FGF)-2, glial cell line–derived neurotrophic factor (GDNF), cRET, wingless-type mouse mammary tumor virus integration site (WNT)4, WNT11, bone morphogenetic protein (BMP)-4, BMP7, and FGF7 were determined by real-time polymerase chain reaction and Western blotting. Results: Maternal food restriction resulted in up-regulated mRNA expression for WT1, FGF2, and BMP7, whereas Pax2, GDNF, FGF7, BMP4, WNT4, and WNT11 mRNAs were down-regulated. Protein expression was concordant for WT1, GDNF, Pax2, FGF7, BMP4, and WNT4. Conclusion: Maternal food restriction altered gene expression of fetal renal transcription and growth factors and likely contributes to development of offspring hypertension. [Copyright &y& Elsevier]

Clinical evidence suggests that intrauterine growth restriction (IUGR) can cause persistent changes in the preference for palatable foods. In this study, we compared food preferences, the response to food rewards, and the role of the mesolimbic dopaminergic system in feeding behavior, between IUGR and control rats. Time-mated pregnant Sprague–Dawley rats were randomly allocated to a control group (standard chow ad libitum) or a 50% food restriction (FR) group, which received 50% of the control dams׳ habitual intake. These diets were provided from gestation day 10 to the 21st day of lactation. Within 24 h of birth, pups were cross-fostered and divided into four groups: Adlib/Adlib, FR/Adlib, FR/FR, Adlib/FR . Standard chow consumption was compared between all groups. Food preferences, conditioned place preference to a palatable diet, and the levels of tyrosine hydroxylase (TH) phosphorylation and D2 receptors in the nucleus accumbens were analyzed and compared between the two groups of interest: Adlib/Adlib (control) and FR/Adlib (exposed to growth restriction during the fetal period only). IUGR adult rats had a stronger preference for palatable foods, but showed less conditioned place preference to a palatable diet than controls. D2 receptors levels were lower in IUGR rats. At baseline, TH and pTH levels were higher in FR/Adlib than control males. Measurements taken after exposure to sweet foods revealed higher levels of TH and pTH in FR/Adlib than control females. These data showed that IUGR rats exhibited a preference for palatable foods, potentially due to alterations in their mesolimbic reward pathway. Additionally, the changes observed in the mesolimbic dopaminergic system of IUGR rats proved to be sex-specific. This article is part of a Special Issue entitled 1618 . [ABSTRACT FROM AUTHOR]