Effects of maternal prenatal undernutrition on the energy metabolism regulation of adult male offspring : focus on hypothalamus and adipose tissue

Des données épidémiologiques indiquent qu’une dénutrition maternelle prénatale (DMP) induit un retard de croissance intra-utérin (RCIU) et prédispose la descendance au développement d’un syndrome métabolique (SM). Afin de comprendre les mécanismes impliqués dans la mise en place du SM, nous avons développé un modèle de restriction alimentaire de 70 % chez le rat pendant toute la gestation : le modèle FR30. Nos travaux montrent que la DMP augmente la sensibilité de la descendance mâle au développement de certains traits du SM tels qu’une hypertension modérée, une hyperleptinémie sans phénotype d’obésité, une hypercorticostéronémie, une perturbation de la régulation de la glycémie, une hyperphagie et de subtiles altérations des projections neuronales à POMC. Notre objectif a été ensuite d’identifier les mécanismes programmés par la DMP chez la descendance mâle FR30 adulte au niveau de l’axe hypothalamo-adipocytaire (HA). Basé sur la théorie de la programmation fœtale, nous avons tenté d’exacerber les perturbations métaboliques observées et/ou silencieuses par un régime hyperlipidique (HF) dès le sevrage. Bien que la DMP n’exacerbe pas les traits de SM induits par le régime HF, les rats FR30HF ont une prise de poids plus importante, une masse de dépôts adipeux augmentée, un taux de leptine plus important et une absence d’augmentation des glucocorticoïdes circulants suite au jeûne. Nous avons montré que le tissu adipeux présente de fortes variations d’expression génique différentes en fonction des dépôts adipeux, contrairement à l’hypothalamus. Nos travaux suggèrent donc que l’axe HA constitue l’une des cibles privilégiées de la programmation fœtale suite à une DMP.Epidemiological studies have shown that maternal undernutrition during pregnancy (MU) leads to intrauterine growth retardation and may predispose individuals to the development of metabolic syndrome. In order to better understand the underlying mechanisms, we have developed a model of prenatal maternal 70% food-restricted diet throughout gestation in pregnant female rats called FR30. Our results show that MU increases the vulnerability to some metabolic syndrome features in adult male rat offspring such as mild hypertension, hyperleptinemia without obesity, hypercorticosteronemia, impaired glucose intolerance and hyperphagia and subtle alterations of POMC hypothalamic neurons projections. Our goal was then to identify tissue mechanisms programmed by MU in FR30 adult male offspring hypothalamic-adipose axis (HA). Based on the developmental origins of the metabolic syndrome, we attempted to heighten visible and/or silent metabolic alterations observed under standard diet by feeding FR30 rats a high fat (HF) diet since the weaning. Although MU does not worsen the metabolic syndrome features induced by postnatal HF feeding, FR30 adult rats gain more weight, exhibit greater body fat content, a rise of serum leptin levels and a blunted increase of corticosterone levels. FR30 MU does not significantly affect the hypothalamic mRNA levels whereas it leads to marked gene expression variation in WAT in depot-specific and diet-specific manners. Our results suggest that the HA tissue axis is one of the key targets of MU fetal programming in adult male rat offspring

Effects of maternal prenatal undernutrition on the energy metabolism regulation of adult male offspring : focus on hypothalamus and adipose tissue

Des données épidémiologiques indiquent qu’une dénutrition maternelle prénatale (DMP) induit un retard de croissance intra-utérin (RCIU) et prédispose la descendance au développement d’un syndrome métabolique (SM). Afin de comprendre les mécanismes impliqués dans la mise en place du SM, nous avons développé un modèle de restriction alimentaire de 70 % chez le rat pendant toute la gestation : le modèle FR30. Nos travaux montrent que la DMP augmente la sensibilité de la descendance mâle au développement de certains traits du SM tels qu’une hypertension modérée, une hyperleptinémie sans phénotype d’obésité, une hypercorticostéronémie, une perturbation de la régulation de la glycémie, une hyperphagie et de subtiles altérations des projections neuronales à POMC. Notre objectif a été ensuite d’identifier les mécanismes programmés par la DMP chez la descendance mâle FR30 adulte au niveau de l’axe hypothalamo-adipocytaire (HA). Basé sur la théorie de la programmation fœtale, nous avons tenté d’exacerber les perturbations métaboliques observées et/ou silencieuses par un régime hyperlipidique (HF) dès le sevrage. Bien que la DMP n’exacerbe pas les traits de SM induits par le régime HF, les rats FR30HF ont une prise de poids plus importante, une masse de dépôts adipeux augmentée, un taux de leptine plus important et une absence d’augmentation des glucocorticoïdes circulants suite au jeûne. Nous avons montré que le tissu adipeux présente de fortes variations d’expression génique différentes en fonction des dépôts adipeux, contrairement à l’hypothalamus. Nos travaux suggèrent donc que l’axe HA constitue l’une des cibles privilégiées de la programmation fœtale suite à une DMP.Epidemiological studies have shown that maternal undernutrition during pregnancy (MU) leads to intrauterine growth retardation and may predispose individuals to the development of metabolic syndrome. In order to better understand the underlying mechanisms, we have developed a model of prenatal maternal 70% food-restricted diet throughout gestation in pregnant female rats called FR30. Our results show that MU increases the vulnerability to some metabolic syndrome features in adult male rat offspring such as mild hypertension, hyperleptinemia without obesity, hypercorticosteronemia, impaired glucose intolerance and hyperphagia and subtle alterations of POMC hypothalamic neurons projections. Our goal was then to identify tissue mechanisms programmed by MU in FR30 adult male offspring hypothalamic-adipose axis (HA). Based on the developmental origins of the metabolic syndrome, we attempted to heighten visible and/or silent metabolic alterations observed under standard diet by feeding FR30 rats a high fat (HF) diet since the weaning. Although MU does not worsen the metabolic syndrome features induced by postnatal HF feeding, FR30 adult rats gain more weight, exhibit greater body fat content, a rise of serum leptin levels and a blunted increase of corticosterone levels. FR30 MU does not significantly affect the hypothalamic mRNA levels whereas it leads to marked gene expression variation in WAT in depot-specific and diet-specific manners. Our results suggest that the HA tissue axis is one of the key targets of MU fetal programming in adult male rat offspring

Effets d'une dénutrition maternelle prénatale sur la régulation de l'homéostasie énergétique chez la descendance mâle adulte (focus sur l'hypothalamus et le tissu adipeux)

Des données épidémiologiques indiquent qu une dénutrition maternelle prénatale (DMP) induit un retard de croissance intra-utérin (RCIU) et prédispose la descendance au développement d un syndrome métabolique (SM). Afin de comprendre les mécanismes impliqués dans la mise en place du SM, nous avons développé un modèle de restriction alimentaire de 70 % chez le rat pendant toute la gestation : le modèle FR30. Nos travaux montrent que la DMP augmente la sensibilité de la descendance mâle au développement de certains traits du SM tels qu une hypertension modérée, une hyperleptinémie sans phénotype d obésité, une hypercorticostéronémie, une perturbation de la régulation de la glycémie, une hyperphagie et de subtiles altérations des projections neuronales à POMC. Notre objectif a été ensuite d identifier les mécanismes programmés par la DMP chez la descendance mâle FR30 adulte au niveau de l axe hypothalamo-adipocytaire (HA). Basé sur la théorie de la programmation fœtale, nous avons tenté d exacerber les perturbations métaboliques observées et/ou silencieuses par un régime hyperlipidique (HF) dès le sevrage. Bien que la DMP n exacerbe pas les traits de SM induits par le régime HF, les rats FR30HF ont une prise de poids plus importante, une masse de dépôts adipeux augmentée, un taux de leptine plus important et une absence d augmentation des glucocorticoïdes circulants suite au jeûne. Nous avons montré que le tissu adipeux présente de fortes variations d expression génique différentes en fonction des dépôts adipeux, contrairement à l hypothalamus. Nos travaux suggèrent donc que l axe HA constitue l une des cibles privilégiées de la programmation fœtale suite à une DMP.Epidemiological studies have shown that maternal undernutrition during pregnancy (MU) leads to intrauterine growth retardation and may predispose individuals to the development of metabolic syndrome. In order to better understand the underlying mechanisms, we have developed a model of prenatal maternal 70% food-restricted diet throughout gestation in pregnant female rats called FR30. Our results show that MU increases the vulnerability to some metabolic syndrome features in adult male rat offspring such as mild hypertension, hyperleptinemia without obesity, hypercorticosteronemia, impaired glucose intolerance and hyperphagia and subtle alterations of POMC hypothalamic neurons projections. Our goal was then to identify tissue mechanisms programmed by MU in FR30 adult male offspring hypothalamic-adipose axis (HA). Based on the developmental origins of the metabolic syndrome, we attempted to heighten visible and/or silent metabolic alterations observed under standard diet by feeding FR30 rats a high fat (HF) diet since the weaning. Although MU does not worsen the metabolic syndrome features induced by postnatal HF feeding, FR30 adult rats gain more weight, exhibit greater body fat content, a rise of serum leptin levels and a blunted increase of corticosterone levels. FR30 MU does not significantly affect the hypothalamic mRNA levels whereas it leads to marked gene expression variation in WAT in depot-specific and diet-specific manners. Our results suggest that the HA tissue axis is one of the key targets of MU fetal programming in adult male rat offspring.LILLE1-Bib. Electronique (590099901) / SudocSudocFranceF

Neonatal hyperoxia leads to white adipose tissue remodeling and susceptibility to hypercaloric diet

Abstract Individuals born preterm are at higher risk of cardiovascular and metabolic diseases in adulthood, through mechanisms not completely understood. White adipose tissue in humans and rodents is a dynamic endocrine organ and a critical player in the regulation of metabolic homeostasis. However, the impact of preterm birth on white adipose tissue remains unknown. Using a well‐established rodent model of preterm birth‐related conditions in which newborn rats are exposed during postnatal days 3–10 to 80% of oxygen, we evaluated the impact of transient neonatal hyperoxia on adult perirenal white adipose tissue (pWAT) and liver. We further assessed the effect of a second hit with a high‐fat high‐fructose hypercaloric diet (HFFD). We evaluated 4‐month‐old adult male rats after 2 months of HFFD. Neonatal hyperoxia led to pWAT fibrosis and macrophage infiltration without modification in body weight, pWAT weight, or adipocyte size. In animals exposed to neonatal hyperoxia vs. room air control, HFFD resulted in adipocyte hypertrophy, lipid accumulation in the liver, and increased circulating triglycerides. Overall, preterm birth‐related conditions had long‐lasting effects on the composition and morphology of pWAT, along with a higher susceptibility to the deleterious impact of a hypercaloric diet. These changes suggest a developmental pathway to long‐term metabolic risk factors observed clinically in adults born preterm through programming of white adipose tissue

Maternal prenatal undernutrition alters the response of POMC neurons to energy status variation in adult male rat offspring.

International audienceEpidemiological 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% food-restricted 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 beta-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 calorie restriction modulates placental mitochondrial biogenesis and bioenergetic efficiency: putative involvement in fetoplacental growth defects in rats

Low birth weight is associated with an increased risk for developing type 2 diabetes and metabolic diseases. The placental capacity to supply nutrients and oxygen to the fetus represents the main determiner of fetal growth. However, few studies have investigated the effects of maternal diet on the placenta. We explored placental adaptive proteomic processes implicated in response to maternal undernutrition. Rat term placentas from 70% food-restricted (FR30) mothers were used for a proteomic screen. Placental mitochondrial functions were evaluated using molecular and functional approaches, and ATP production was measured. FR30 drastically reduced placental and fetal weights. FR30 placentas displayed 14 proteins that were differentially expressed, including several mitochondrial proteins. FR30 induced a marked increase in placental mtDNA content and changes in mitochondrial functions, including modulation of the expression of genes implicated in biogenesis and bioenergetic pathways. FR30 mitochondria showed higher oxygen consumption but failed to maintain their ATP production. Maternal undernutrition induces placental mitochondrial abnormalities. Although an increase in biogenesis and bioenergetic efficiency was noted, placental ATP level was reduced. Our data suggest that placental mitochondrial defects may be implicated in fetoplacental pathologies