-Several studies have shown that maternal undernutrition leading to low birth weight predisposes offspring to the development of metabolic pathologies such as obesity. Using a model of prenatal maternal 70% food restriction diet (FR30) in rat, we evaluated whether postweaning high-fat (HF) diet would amplify the phenotype observed under standard diet. We investigated biological parameters as well as gene expression profile focusing on white adipose tissues (WAT) of adult offspring. FR30 procedure does not worsen the metabolic syndrome features induced by HF diet. However, FR30HF rats displayed catch-up growth to match the body weight of adult control HF animals, suggesting an increase of adiposity while showing hyperleptinemia and a blunted increase of corticosterone. Using quantitative RT-PCR array, we demonstrated that FR30HF rats exhibited leptin and Ob-Rb as well as many peptide precursor and receptor gene expression variations in WAT. We also showed that the expression of genes involved in adipogenesis was modified in FR30HF animals in a depot-specific manner. We observed an opposite variation of STAT3 phosphorylation levels, suggesting that leptin sensitivity is modified in WAT adult FR30 offspring. We demonstrated that 11␤-HSD1, 11␤-HSD2, GR, and MR genes are coexpressed in WAT and that FR30 procedure modifies gene expression levels, especially under HF diet.

demiological studies suggest that maternal undernutrition predisposes the offspring to development of energy balance metabolic pathologies in adulthood. Using a model of a prenatal maternal 70% foodrestricted diet (FR30) in rats, we evaluated peripheral parameters involved in nutritional regulation, as well as the hypothalamic appetite-regulatory system, in nonfasted and 48-h-fasted adult offspring. Despite comparable glycemia in both groups, mild glucose intolerance, with a defect in glucose-induced insulin secretion, was observed in FR30 animals. They also exhibited hyperleptinemia, despite similar visible fat deposits. Using semiquantitative RT-PCR, we observed no basal difference of hypothalamic proopiomelanocortin (POMC) and neuropeptide Y (NPY) gene expression, but a decrease of the OB-Rb and an increase of insulin receptor mRNA levels, in FR30 animals. These animals also exhibited basal hypercorticosteronemia and a blunted increase of corticosterone in fasted compared with control animals. After fasting, FR30 animals showed no marked reduction of POMC mRNA levels or intensity of ␤-endorphin-immunoreactive fiber projections. By contrast, NPY gene expression and immunoreactive fiber intensity increased. FR30 rats also displayed subtle alterations of food intake: body weight-related food intake was higher and light-dark phase rhythm and refeeding time course were modified after fasting. At rest, in the morning, hyperinsulinemia and a striking increase in the number of c-Fos-containing cells in the arcuate nucleus were observed. About 30% of the c-Fos-expressing cells were POMC neurons. Our data suggest that maternal undernutrition differently programs the long-term appetite-regulatory system of offspring, especially the response of POMC neurons to energy status and food intake rhythm. maternal undernutrition; appetite programming; hypothalamus; arcuate nucleus; feeding rhythm IN ADDITION TO LIFESTYLE and dietary factors, increasing evidence suggests that the origin of some metabolic disorders that manifest in adult life may be traced to development. Indeed, epidemiological studies have shown that adverse environmental factors leading to intrauterine growth retardation (IUGR) and low birth weight may predispose individuals to later onset of energy balance metabolic pathology development (9,17,18,20,29). This has led to the concept of the developmental origin of adult diseases, also called "fetal programming," or the Barker hypothesis (4). As illustrated by the Dutch Famine Study, offspring of women exposed to famine during early pregnancy displayed an increased risk of adiposity and glucose intolerance, as well as hypertension, later in life (41).To obtain insights into the underlying mechanisms, numerous animal models, including maternal undernutrition, have been developed to promote intrauterine fetal programming (47,56). These studies confirmed that impaired fetal development has long-term metabolic consequences, sensitizing the offspring to hyperphagia and obesity, particularly when they are fed a hyperca...

No abstract

Several studies indicate that maternal undernutrition sensitizes the offspring to the development of metabolic disorders, such as obesity. Using a model of perinatal maternal 50% food-restricted diet (FR50), we recently reported that rat neonates from undernourished mothers exhibit decreased leptin plasma levels associated with alterations of hypothalamic proopiomelanocortin system. The present study aimed at examining the consequences of FR50 on the brain-adipose axis in male rat neonates. Using quantitative RT-PCR array containing 84 obesity-related genes, we demonstrated that most of the genes involved in energy metabolism regulation are expressed in rat gonadal white adipose tissue (WAT) and are sensitive to maternal perinatal undernutrition (MPU). In contrast, hypothalamic gene expression was not substantially affected by MPU. Gene expression of uncoupling protein 1 (UCP1), a marker of brown adipocytes, showed an almost 400-fold stimulation in postnatal day 21 (PND21) FR50 animals, suggesting that their gonadal WAT possesses a brown-like phenotype. This was confirmed by histological and immunoshistochemical procedures, which demonstrated that PND21 FR50 gonadal adipocytes are multilocular, resembling those present in interscapular brown adipose tissue, and exhibit an overexpression of UCP1 and neuropeptide Y (NPY) at the protein level. Control animals contained almost exclusively "classical" unilocular white adipocytes that did not show high UCP1 and NPY labeling. After weaning, FR50 animals exhibited a transient hyperphagia that was associated with the disappearance of brown-like fat pads in PND30 WAT. Our results demonstrate that MPU delays the maturation of gonadal WAT during critical developmental time windows, suggesting that it could have long-term consequences on body weight regulation in the offspring.

R enin-angiotensin system (RAS) is a key component of cardiovascular and renal system homeostasis. RAS activation during development is well described 1 and contributes to organogenesis and growth, especially in the cardiovascular and renal systems. Among RAS components, angiotensin (Ang) II is the major peptide acting during fetal and neonatal life. Both subtypes of Ang receptors are expressed during fetal development 2,3 but have different patterns of expression during the fetal-neonatal transition. In rats, Ang type 2 (AT2) receptors are upregulated in the heart, large vessels, lungs, and kidneys during fetal development and progressively decline after birth, suggesting their contribution to fetal organogenesis. Ang type 1 (AT1) receptors, on the other hand, are detected late in fetal development, increase soon after birth, and are considered to contribute mainly to tissue maturation, growth, and postnatal adaptation. [2][3][4] This switching pattern of Ang receptors suggests that modifications of AT1/AT2 balance play a key role in different developmental stages. A disruption of this balance, depending on the stage of development, may negatively affect cardiovascular and renal homeostasis and contribute to the establishment of cardiovascular diseases.Deleterious perinatal conditions, including preeclampsia, intrauterine growth restriction, and preterm birth can lead to developmental programming of cardiovascular risk factors and diseases. 5,6 Preterm-born individuals in particular, whose numbers are growing in the population because of recent Abstract-Newborn rats exposed to high oxygen (O 2 ), mimicking preterm birth-related neonatal stress, develop later in life cardiac hypertrophy, dysfunction, fibrosis, and activation of the renin-angiotensin system. Cardiac renin-angiotensin system activation in O 2 -exposed adult rats is characterized by an imbalance in angiotensin (Ang) receptors type 1/2 (AT1/2), with prevailing AT1 expression. To study the role of renin-angiotensin system in the developmental programming of cardiac dysfunction, we assessed Ang receptor expression during neonatal high O 2 exposure and whether AT1 receptor blockade prevents cardiac alterations in early adulthood. Sprague-Dawley newborn rats were kept with their mother in 80% O 2 or room air (control) from days 3 to 10 (P3-P10) of life. Losartan or water was administered by gavage from P8 to P10 (n=9/group). Rats were studied at P3 (before O 2 exposure), P5, P10 (end of O 2 ), and P28. Losartan treatment had no impact on growth or kidney development. AT1 and Ang type 2 receptors were upregulated in the left ventricle by high O 2 exposure (P5 and P10), which was prevented by Losartan treatment at P10. Losartan prevented the cardiac AT1/2 imbalance at P28. Losartan decreased cardiac hypertrophy and fibrosis and improved left ventricle fraction of shortening in P28 O 2 -exposed rats, which was associated with decreased oxidation of calcium/calmodulin-dependent protein kinase II, inhibition of the transforming growth factor-β/SMAD3 pathway...

No abstract

Preterm neonates are prematurely exposed to high oxygen levels at birth which may adversely impact ongoing renal development. The aim of this study was to determine the effects of neonatal hyperoxia exposure on renal function and morphology with aging. Sprague Dawley rat pups were raised in a hyperoxic environment (80% oxygen) from P3 to P10 during ongoing postnatal nephrogenesis. Control litters were kept in room air (n = 6–8 litters/group; one male, one female/litter/age). Kidney function (urine and plasma creatinine, sodium, and protein) and morphology (renal corpuscle size, glomerulosclerosis, fibrosis, and glomerular crescents) were assessed at 1, 5, and 11 months of age. Neonatal hyperoxia exposure had no impact on body or kidney weights. Creatinine clearance was significantly reduced following hyperoxia exposure at 5 months; there was no significant effect on renal function at 1 or 11 months. The percentage of crescentic glomeruli (indicative of glomerular injury) was markedly increased in 11 month hyperoxia‐exposed males. Renal corpuscle size, glomerulosclerosis index, and renal fibrosis were not affected. Findings suggest that exposure to high oxygen levels during development may impact renal functional capacity and increase susceptibility to renal disease in adulthood depending on age and sex.

Epidemiological studies initially suggested that maternal undernutrition leading to low birth weight may predispose for long-lasting energy balance disorders. High birth weight due to maternal obesity or diabetes, inappropriate early postnatal nutrition, and rapid catch-up growth, may also sensitize to increased risk of obesity. As stated by the Developmental Origin of Health and Disease concept, the perinatal perturbation of fetus/neonate nutrient supply might be a crucial determinant of individual programming of body weight set-point. The hypothalamic melanocortin system composed of the melanocortin receptor 4, its agonist α-melanin-stimulating hormone (α-MSH), and its antagonist agouti-related protein (AgRP) is considered as the main central anorexigenic pathway controlling energy homeostasis. Studies in numerous animal models demonstrated that this system is a prime target of developmental programming by maternal nutritional manipulation. In rodents, the perinatal period of life corresponds largely to the period of brain maturation (i. e., melanocortin neuronal differentiation and development of their neural projections). In contrast, these phenomena essentially take place before birth in bigger mammals. Despite these different developmental time windows, altricial and precocial species share several common offspring programming mechanisms. Offspring from malnourished dams present a hypothalamic melanocortin system with a series of alterations: impaired neurogenesis and neuronal functionality, disorganization of feeding pathways, modified glucose sensing, and leptin/insulin resistance. Overall, these alterations may account for the long-lasting dysregulation of energy balance and obesity. Following maternal malnutrition, hormonal and epigenetic mechanisms might be responsible for melanocortin system programming in offspring.