Intrauterine growth disturbance and metabolic programming : implication of the Rho-kinase pathway and of the apelinergic system in rodents

Durant ces dernières années, de nombreuses études épidémiologiques ont mis en évidence que les pathologies métaboliques (obésité, diabète) et cardiovasculaires pourraient, en partie, se déterminer dès la grossesse, via des perturbations de l’environnement intra-utérin. La notion de « programmation fœtale » implique qu’une altération durant la vie fœtale perturberait le développement du fœtus et le vulnérabiliserait au développement ultérieur de pathologies. Ainsi, un enfant qui naît avec un très faible poids de naissance (inférieur à 2,4 kg) ou à l’inverse avec un poids de naissance très élevé (supérieur à 4,0 kg) est statistiquement plus vulnérable au développement de ces maladies. Pour étudier ce phénomène et tenter d’en comprendre les mécanismes, nous avons utilisé des modèles expérimentaux (rat, souris) et évalué l’action et l’expression de deux substances vasodilatatrices : le Fasudil (un inhibiteur des Rho kinases) et l’hormone apeline. Les rates gestantes traitées par le L-NAME, un inhibiteur de la NO synthase (50 mg/jour) présentaient une hypertension artérielle et leurs nouveau-nés un retard de croissance intra-utérin (RCIU) de l’ordre de 20%. L’administration aux mères de Fasudil (10 mg/jour) permettait de restaurer une pression artérielle normale en fin de gestation et améliorait considérablement la croissance fœtale des animaux exposés au L-NAME. Cependant, alors que les animaux nés avec un RCIU (nouveau-nés L-NAME) ne présentaient que peu de perturbations métaboliques à l’âge adulte, les animaux exposés au Fasudil seul étaient rapidement en surpoids, présentaient une hyperglycémie à jeun et développaient des troubles du comportement alimentaire de type hyperphagique. D’autre part, par une étude menée chez des souris obèses et intolérantes au glucose après exposition à un régime hyperlipidique, nous avons démontré que l’expression génique de l’apeline est altérée dans plusieurs organes (foie, rein, tissu adipeux) bien que l’apelinémie des souris obèses reste inchangée. Des études en voie de finalisation sont menées afin de déterminer si le système apelinergique est modulé chez des souris gestantes obèses à la fois chez les compartiments maternels et fœtaux mais aussi dans le placenta. En conclusion, nous avons démontré que l’inhibition de la voie des Rho kinases en fin de gestation programme chez la descendance un surpoids, une hyperglycémie et à une altération de la prise alimentaire. Ayant démontré que le système apelinergique est altéré chez des souris femelles obèses et intolérantes au glucose, il nous reste à déterminer si ce système est aussi perturbé en condition de grossesse associée à l’obésité maternelle.During the last decade, many epidemiological studies have shown that adult chronic metabolic (obesity, diabetes) and cardiovascular diseases may be determined, at least in part, during pregnancy through alterations of intrauterine environment. The “fetal programming” hypothesis implies that disturbances of the fetal development (intra uterine growth restriction – IUGR or macrosomia) increase the vulnerability to develop these pathologies in adulthood. To gain more insight into the mechanisms implicated in fetal programming, we used two experimental models of rodents (rat, mouse) and evaluated first the effect of an inhibition of the Rho-kinase pathway in utero on fetal growth and postnatal development in rats. In another study performed in mice, we aimed to assess the expression of apelin and its receptor APJ in obese and glucose intolerant mice fed with a high fat diet. Using data of this preliminary study, we speculated that this signaling system may be targeted during the pregnancy of obese mothers and could be implicated into the physiopathological consequences that may affect the fetoplacental unit. We demonstrated that pregnant rats treated by L-NAME, a NO synthase inhibitor (50 mg/day) were hypertensive and that their newborns presented a dramatic IUGR. Maternal treatment with the vasodilator Fasudil (10 mg/day) restored a normal maternal blood pressure and remarkably alleviated the fetal growth of L-NAME newborns. In adults, L-NAME male rats developed mild metabolic pathologies whereas rats exposed in utero to Fasudil presented an overweight, with hyperphagia and glucose intolerance. In obese and glucose intolerant mice fed with a high fat diet, we showed that apelin gene expression was altered in several organs (liver, kidney and adipose tissue) without any variation of apelin plasma concentration. Further studies are currently performed in our laboratory to unravel the expression of the apelin/APJ pathway in pregnant obese mice and their offsprings

Altération de la croissance fœtale et programmation métabolique : étude de l’implication des Rho-kinases et du système apelinergique chez les rongeurs

During the last decade, many epidemiological studies have shown that adult chronic metabolic (obesity, diabetes) and cardiovascular diseases may be determined, at least in part, during pregnancy through alterations of intrauterine environment. The “fetal programming” hypothesis implies that disturbances of the fetal development (intra uterine growth restriction – IUGR or macrosomia) increase the vulnerability to develop these pathologies in adulthood. To gain more insight into the mechanisms implicated in fetal programming, we used two experimental models of rodents (rat, mouse) and evaluated first the effect of an inhibition of the Rho-kinase pathway in utero on fetal growth and postnatal development in rats. In another study performed in mice, we aimed to assess the expression of apelin and its receptor APJ in obese and glucose intolerant mice fed with a high fat diet. Using data of this preliminary study, we speculated that this signaling system may be targeted during the pregnancy of obese mothers and could be implicated into the physiopathological consequences that may affect the fetoplacental unit. We demonstrated that pregnant rats treated by L-NAME, a NO synthase inhibitor (50 mg/day) were hypertensive and that their newborns presented a dramatic IUGR. Maternal treatment with the vasodilator Fasudil (10 mg/day) restored a normal maternal blood pressure and remarkably alleviated the fetal growth of L-NAME newborns. In adults, L-NAME male rats developed mild metabolic pathologies whereas rats exposed in utero to Fasudil presented an overweight, with hyperphagia and glucose intolerance. In obese and glucose intolerant mice fed with a high fat diet, we showed that apelin gene expression was altered in several organs (liver, kidney and adipose tissue) without any variation of apelin plasma concentration. Further studies are currently performed in our laboratory to unravel the expression of the apelin/APJ pathway in pregnant obese mice and their offsprings.Durant ces dernières années, de nombreuses études épidémiologiques ont mis en évidence que les pathologies métaboliques (obésité, diabète) et cardiovasculaires pourraient, en partie, se déterminer dès la grossesse, via des perturbations de l’environnement intra-utérin. La notion de « programmation fœtale » implique qu’une altération durant la vie fœtale perturberait le développement du fœtus et le vulnérabiliserait au développement ultérieur de pathologies. Ainsi, un enfant qui naît avec un très faible poids de naissance (inférieur à 2,4 kg) ou à l’inverse avec un poids de naissance très élevé (supérieur à 4,0 kg) est statistiquement plus vulnérable au développement de ces maladies. Pour étudier ce phénomène et tenter d’en comprendre les mécanismes, nous avons utilisé des modèles expérimentaux (rat, souris) et évalué l’action et l’expression de deux substances vasodilatatrices : le Fasudil (un inhibiteur des Rho kinases) et l’hormone apeline. Les rates gestantes traitées par le L-NAME, un inhibiteur de la NO synthase (50 mg/jour) présentaient une hypertension artérielle et leurs nouveau-nés un retard de croissance intra-utérin (RCIU) de l’ordre de 20%. L’administration aux mères de Fasudil (10 mg/jour) permettait de restaurer une pression artérielle normale en fin de gestation et améliorait considérablement la croissance fœtale des animaux exposés au L-NAME. Cependant, alors que les animaux nés avec un RCIU (nouveau-nés L-NAME) ne présentaient que peu de perturbations métaboliques à l’âge adulte, les animaux exposés au Fasudil seul étaient rapidement en surpoids, présentaient une hyperglycémie à jeun et développaient des troubles du comportement alimentaire de type hyperphagique. D’autre part, par une étude menée chez des souris obèses et intolérantes au glucose après exposition à un régime hyperlipidique, nous avons démontré que l’expression génique de l’apeline est altérée dans plusieurs organes (foie, rein, tissu adipeux) bien que l’apelinémie des souris obèses reste inchangée. Des études en voie de finalisation sont menées afin de déterminer si le système apelinergique est modulé chez des souris gestantes obèses à la fois chez les compartiments maternels et fœtaux mais aussi dans le placenta. En conclusion, nous avons démontré que l’inhibition de la voie des Rho kinases en fin de gestation programme chez la descendance un surpoids, une hyperglycémie et à une altération de la prise alimentaire. Ayant démontré que le système apelinergique est altéré chez des souris femelles obèses et intolérantes au glucose, il nous reste à déterminer si ce système est aussi perturbé en condition de grossesse associée à l’obésité maternelle

PPAR control of metabolism and cardiovascular functions

International audiencePeroxisome proliferator-activated receptor-α (PPARα), PPARδ and PPARγ are transcription factors that regulate gene expression following ligand activation. PPARα increases cellular fatty acid uptake, esterification and trafficking and regulates lipoprotein metabolism genes. PPARδ stimulates lipid and glucose utilization by increasing mitochondrial function and fatty acid desaturation pathways. By contrast, PPARγ promotes fatty acid uptake, triglyceride formation and storage in lipid droplets, thereby improving insulin sensitivity and glucose metabolism. PPARs also exert anti-atherogenic and anti-inflammatory effects on the vascular wall and immune cells. Clinically, PPARγ activation by glitazones and PPARα activation by fibrates improve insulin resistance and dyslipidaemia, respectively. PPARs are also physiological master switches in the heart, steering cardiac energy metabolism in cardiomyocytes, thereby affecting pathological heart failure and diabetic cardiomyopathy. Novel PPAR agonists in clinical development are providing new opportunities in the management of metabolic and cardiovascular diseases

Treating NASH by targeting peroxisome proliferator- activated receptors

Abstract: The pathophysiology of non-alcoholic steatohepatitis (NASH) encompasses a complex set of intra-and extrahepatic driving mechanisms, involving numerous metabolic, inflammatory, vascular and fibrogenic pathways. The peroxisome proliferatoractivated receptors (PPARs) a, b/d and c belong to the nuclear receptor family of ligand-activated transcription factors. Activated PPARs modulate target tissue transcriptomic profiles, enabling the body's adaptation to changing nutritional, metabolic and inflammatory environments. PPARs hence regulate several pathways involved in NASH pathogenesis. Whereas single PPAR agonists exert robust anti-NASH activity in several preclinical models, their clinical effects on histological endpoints of NASH resolution and fibrosis regression appear more modest. Simultaneous activation of several PPAR isotypes across different organs and within-organ cell types, resulting in pleiotropic actions, enhances the therapeutic potential of PPAR agonists as pharmacological agents for NASH and NASH-related hepatic and extrahepatic morbidity, with some compounds having already shown clinical efficacy on histological endpoints.(c) 2023 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved

Sensitivity to the photoperiod and potential migratory features of neuroblasts in the adult sheep hypothalamus

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The apelinergic system: Sexual dimorphism and tissue-specific modulations by obesity and insulin resistance in female mice.

International audienceIt has been proposed that the apelinergic system (apelin and its receptor APJ) may be a promising therapeutic target in obesity-associated insulin resistance syndrome. However, due to the extended tissue-distribution of this system, the therapeutic use of specific ligands for APJ may target numerous tissues resulting putatively to collateral deleterious effects. To unravel specific tissular dysfunctions of this system under obesity and insulin-resistance conditions, we measured the apelinemia and gene-expression level of both apelin (APL) and APJ in 12-selected tissues of insulin-resistant obese female mice fed with a high fat (HF) diet. In a preliminary study, we compared between adult male and female mice, the circadian plasma apelin variation and the effect of fasting on apelinemia. No significant differences were found for these parameters suggesting that the apelinemia is not affected by the sex. Moreover, plasma apelin level was not modulated during the four days of the estrous cycle in females. In obese and insulin-resistant HF female mice, plasma apelin concentration after fasting was not modified but, the gene-expression level of the APL/APJ system was augmented in the white adipose tissue (WAT) and reduced in the brown adipose tissue (BAT), the liver and in kidneys. BAT apelin content was reduced in HF female mice. Our data suggest that the apelinergic system may be implicated into specific dysfunctions of these tissues under obesity and diabetes and that, pharmacologic modulations of this system may be of interest particularly in the treatment of adipose, liver and renal dysfunctions that occur during these pathologies

Maternal hypertension induces tissue-specific modulations of the apelinergic system in the fetoplacental unit in rat.

International audienceApelin and its receptor APJ are expressed in fetal tissues but their function and regulation remain largely unknown. In rat, maternal treatment with a nitric oxide synthase inhibitor inducing hypertension was used to investigate apelin plasma levels in mother/fetus pairs and on the gene expression level of the apelin/APJ system in fetal tissues and placenta. At term, plasma levels of apelin were not modulated but APJ expression was increased in placenta and lung but reduced in heart. Apelin expression was increased only in the heart. We postulate that the apelinergic system may control fetal growth and cardiovascular functions in utero

Pineal-dependent increase of hypothalamic neurogenesis contributes to the timing of seasonal reproduction in sheep

Abstract To survive in temperate latitudes, species rely on the photoperiod to synchronize their physiological functions, including reproduction, with the predictable changes in the environment. In sheep, exposure to decreasing day length reactivates the hypothalamo-pituitary-gonadal axis, while during increasing day length, animals enter a period of sexual rest. Neural stem cells have been detected in the sheep hypothalamus and hypothalamic neurogenesis was found to respond to the photoperiod. However, the physiological relevance of this seasonal adult neurogenesis is still unexplored. This longitudinal study, therefore aimed to thoroughly characterize photoperiod-stimulated neurogenesis and to investigate whether the hypothalamic adult born-cells were involved in the seasonal timing of reproduction. Results showed that time course of cell proliferation reached a peak in the middle of the period of sexual activity, corresponding to decreasing day length period. This enhancement was suppressed when animals were deprived of seasonal time cues by pinealectomy, suggesting a role of melatonin in the seasonal regulation of cell proliferation. Furthermore, when the mitotic blocker cytosine-b-D-arabinofuranoside was administered centrally, the timing of seasonal reproduction was affected. Overall, our findings link the cyclic increase in hypothalamic neurogenesis to seasonal reproduction and suggest that photoperiod-regulated hypothalamic neurogenesis plays a substantial role in seasonal reproductive physiology

Maternal PUFA ω-3 Supplementation Prevents Neonatal Lung Injuries Induced by Hyperoxia in Newborn Rats

Bronchopulmonary dysplasia (BPD) is one of the most common complications of prematurity, occurring in 30% of very low birth weight infants. The benefits of dietary intake of polyunsaturated fatty acids ω-3 (PUFA ω-3) during pregnancy or the perinatal period have been reported. The aim of this study was to assess the effects of maternal PUFA ω-3 supplementation on lung injuries in newborn rats exposed to prolonged hyperoxia. Pregnant female Wistar rats (n = 14) were fed a control diet (n = 2), a PUFA ω-6 diet (n = 6), or a PUFA ω-3 diet (n = 6), starting with the 14th gestation day. At Day 1, female and newborn rats (10 per female) were exposed to hyperoxia (O2, n = 70) or to the ambient air (Air, n = 70). Six groups of newborns rats were obtained: PUFA ω-6/O2 (n = 30), PUFA ω-6/air (n = 30), PUFA ω-3/O2 (n = 30), PUFA ω-3/air (n = 30), control/O2 (n = 10), and control/air (n = 10). After 10 days, lungs were removed for analysis of alveolarization and pulmonary vascular development. Survival rate was 100%. Hyperoxia reduced alveolarization and increased pulmonary vascular wall thickness in both control (n = 20) and PUFA ω-6 groups (n = 60). Maternal PUFA ω-3 supplementation prevented the decrease in alveolarization caused by hyperoxia (n = 30) compared to PUFA ω-6/O2 (n = 30) or to the control/O2 (n = 10), but did not significantly increase the thickness of the lung vascular wall. Therefore, maternal PUFA ω-3 supplementation may protect newborn rats from lung injuries induced by hyperoxia. In clinical settings, maternal PUFA ω-3 supplementation during pregnancy and during lactation may prevent BPD development after premature birth