Publications by authors named "Laura Butruille"

21 Publications

  • Page 1 of 1

PPAR control of metabolism and cardiovascular functions.

Nat Rev Cardiol 2021 Jun 14. Epub 2021 Jun 14.

University of Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France.

Peroxisome 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 increasing insulin sensitivity and glucose metabolism. PPARs also exert antiatherogenic and anti-inflammatory effects on the vascular wall and immune cells. Clinically, PPARγ activation by glitazones and PPARα activation by fibrates reduce 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.
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http://dx.doi.org/10.1038/s41569-021-00569-6DOI Listing
June 2021

Breast milk apelin level increases with maternal obesity and high-fat feeding during lactation.

Int J Obes (Lond) 2021 May 16;45(5):1052-1060. Epub 2021 Feb 16.

Univ. Lille, EA4489 Environnement Périnatal et Santé, Lille, France.

Objective: Recent evidence indicates that levels of breast milk (BM) hormones such as leptin can fluctuate with maternal adiposity, suggesting that BM hormones may signal maternal metabolic and nutritional environments to offspring during postnatal development. The hormone apelin is highly abundant in BM but its regulation during lactation is completely unknown. Here, we evaluated whether maternal obesity and overnutrition impacted BM apelin and leptin levels in clinical cohorts and lactating rats.

Methods: BM and plasma samples were collected from normal-weight and obese breastfeeding women, and from lactating rats fed a control or a high fat (HF) diet during lactation. Apelin and leptin levels were assayed by ELISA. Mammary gland (MG) apelin expression and its cellular localization in lactating rats was measured by quantitative RT-PCR and immunofluorescence, respectively.

Results: BM apelin levels increased with maternal BMI, whereas plasma apelin levels decreased. BM apelin was also positively correlated with maternal insulin and C-peptide levels. In rats, maternal HF feeding exclusively during lactation was sufficient to increase BM apelin levels and decrease its plasma concentration without changing body weight. In contrast, BM leptin levels increased with maternal BMI in humans, but did not change with maternal HF feeding during lactation in rats. Apelin is highly expressed in the rat MG during lactation and was mainly localized to mammary myoepithelial cells. We found that MG apelin gene expression was up-regulated by maternal HF diet and positively correlated with BM apelin content and maternal insulinemia.

Conclusions: Our study indicates that BM apelin levels increase with long- and short-term overnutrition, possibly via maternal hyperinsulinemia and transcriptional upregulation of MG apelin expression in myoepithelial cells. Apelin regulates many physiological processes, including energy metabolism, digestive function, and development. Further studies are needed to unravel the consequences of such changes in offspring development.
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http://dx.doi.org/10.1038/s41366-021-00772-yDOI Listing
May 2021

Beyond the Rule of 5: Impact of PEGylation with Various Polymer Sizes on Pharmacokinetic Properties, Structure-Properties Relationships of mPEGylated Small Agonists of TGR5 Receptor.

J Med Chem 2021 02 20;64(3):1593-1610. Epub 2021 Jan 20.

Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, EGID, F-59000 Lille, France.

PEGylation of therapeutic agents is known to improve the pharmacokinetic behavior of macromolecular drugs and nanoparticles. In this work, we performed the conjugation of polyethylene glycols (220-5000 Da) to a series of non-steroidal small agonists of the bile acids receptor TGR5. A suitable anchoring position on the agonist was identified to retain full agonistic potency with the conjugates. We describe herein an extensive structure-properties relationships study allowing us to finely describe the non-linear effects of the PEG length on the physicochemical as well as the and pharmacokinetic properties of these compounds. When appending a PEG of suitable length to the TGR5 pharmacophore, we were able to identify either systemic or gut lumen-restricted TGR5 agonists.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01774DOI Listing
February 2021

Opioid effect on the autonomic nervous system in a fetal sheep model.

Arch Gynecol Obstet 2021 Jul 2;304(1):73-80. Epub 2021 Jan 2.

ULR 2694, METRICS, Evaluation des Technologies de Santé et des Pratiques Médicales, University of Lille, 59000, Lille, France.

Purpose: Opioid use during labour can interfere with cardiotocography patterns. Heart rate variability indirectly reflects a fluctuation in the autonomic nervous system and can be monitored through time and spectral analyses. This experimental study aimed to evaluate the impact of nalbuphine administration on the gasometric, cardiovascular, and autonomic nervous system responses in fetal sheep.

Methods: This was an experimental study on chronically instrumented sheep fetuses (surgery at 128 ± 2 days of gestational age, term = 145 days). The model was based on a maternal intravenous bolus injection of nalbuphine, a semisynthetic opioid used as an analgesic during delivery. Fetal gasometric parameters (pH, pO, pCO, and lactates), hemodynamic parameters (fetal heart rate and mean arterial pressure), and autonomic nervous system tone (short-term and long-term variation, low-frequency domain, high-frequency domain, and fetal stress index) were recorded. Data obtained at 30-60 min after nalbuphine injection were compared to those recorded at baseline.

Results: Eleven experiments were performed. Fetal heart rate, mean arterial pressure, and activities at low and high frequencies were stable after injection. Short-term variation decreased at T30 min (P = 0.02), and long-term variation decreased at T60 min (P = 0.02). Fetal stress index gradually increased and reached significance at T60 min (P = 0.02). Fetal gasometric parameters and lactate levels remained stable.

Conclusion: Maternal nalbuphine use during labour may lead to fetal heart changes that are caused by the effect of opioid on the autonomic nervous system; these fluctuations do not reflect acidosis.
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http://dx.doi.org/10.1007/s00404-020-05917-4DOI Listing
July 2021

The nuclear receptor FXR inhibits Glucagon-Like Peptide-1 secretion in response to microbiota-derived Short-Chain Fatty Acids.

Sci Rep 2020 01 13;10(1):174. Epub 2020 Jan 13.

Université de Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011- EGID, F-59000, Lille, France.

The gut microbiota participates in the control of energy homeostasis partly through fermentation of dietary fibers hence producing short-chain fatty acids (SCFAs), which in turn promote the secretion of the incretin Glucagon-Like Peptide-1 (GLP-1) by binding to the SCFA receptors FFAR2 and FFAR3 on enteroendocrine L-cells. We have previously shown that activation of the nuclear Farnesoid X Receptor (FXR) decreases the L-cell response to glucose. Here, we investigated whether FXR also regulates the SCFA-induced GLP-1 secretion. GLP-1 secretion in response to SCFAs was evaluated ex vivo in murine colonic biopsies and in colonoids of wild-type (WT) and FXR knock-out (KO) mice, in vitro in GLUTag and NCI-H716 L-cells activated with the synthetic FXR agonist GW4064 and in vivo in WT and FXR KO mice after prebiotic supplementation. SCFA-induced GLP-1 secretion was blunted in colonic biopsies from GW4064-treated mice and enhanced in FXR KO colonoids. In vitro FXR activation inhibited GLP-1 secretion in response to SCFAs and FFAR2 synthetic ligands, mainly by decreasing FFAR2 expression and downstream Gαq-signaling. FXR KO mice displayed elevated colonic FFAR2 mRNA levels and increased plasma GLP-1 levels upon local supply of SCFAs with prebiotic supplementation. Our results demonstrate that FXR activation decreases L-cell GLP-1 secretion in response to inulin-derived SCFA by reducing FFAR2 expression and signaling. Inactivation of intestinal FXR using bile acid sequestrants or synthetic antagonists in combination with prebiotic supplementation may be a promising therapeutic approach to boost the incretin axis in type 2 diabetes.
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http://dx.doi.org/10.1038/s41598-019-56743-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957696PMC
January 2020

Maternal high-fat diet during suckling programs visceral adiposity and epigenetic regulation of adipose tissue stearoyl-CoA desaturase-1 in offspring.

Int J Obes (Lond) 2019 12 8;43(12):2381-2393. Epub 2019 Jan 8.

Univ. Lille, EA4489, Équipe Malnutrition Maternelle et Programmation des Maladies Métaboliques, F-59000, Lille, France.

Objective: The lactation-suckling period is critical for white adipose tissue (WAT) development. Early postnatal nutrition influences later obesity risk but underlying mechanisms remain elusive. Here, we tested whether altered postnatal nutrition specifically during suckling impacts epigenetic regulation of key metabolic genes in WAT and alter long-term adiposity set point.

Methods: We analyzed the effects of maternal high-fat (HF) feeding in rats exclusively during lactation-suckling on breast milk composition and its impact on male offspring visceral epidydimal (eWAT) and subcutaneous inguinal (iWAT) depots during suckling and in adulthood.

Results: Maternal HF feeding during lactation had no effect on mothers' body weight (BW) or global breast milk composition, but induced qualitative changes in breast milk fatty acid (FA) composition (high n-6/n-3 polyunsaturated FA ratio and low medium-chain FA content). During suckling, HF neonates showed increased BW and mass of both eWAT and iWAT depot but only eWAT displayed an enhanced adipogenic transcriptional signature. In adulthood, HF offspring were predisposed to weight gain and showed increased hyperplastic growth only in eWAT. This specific eWAT expansion was associated with increased expression and activity of stearoyl-CoA desaturase-1 (SCD1), a key enzyme of FA metabolism. SCD1 converts saturated FAs, e.g. palmitate and stearate, to monounsaturated FAs, palmitoleate and oleate, which are the predominant substrates for triglyceride synthesis. Scd1 upregulation in eWAT was associated with reduced DNA methylation in Scd1 promoter surrounding a PPARγ-binding region. Conversely, changes in SCD1 levels and methylation were not observed in iWAT, coherent with a depot-specific programming.

Conclusions: Our data reveal that maternal HF feeding during suckling programs long-term eWAT expansion in part by SCD1 epigenetic reprogramming. This programming events occurred with drastic changes in breast milk FA composition, suggesting that dietary FAs are key metabolic programming factors in the early postnatal period.
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http://dx.doi.org/10.1038/s41366-018-0310-zDOI Listing
December 2019

Reduced PPARγ2 expression in adipose tissue of male rat offspring from obese dams is associated with epigenetic modifications.

FASEB J 2018 05 8;32(5):2768-2778. Epub 2018 Jan 8.

Equipe Malnutrition Maternelle et Programmation des Maladies Métaboliques, Equipe d'Accueil (EA) 4489, University of Lille, Lille, France.

According to the Developmental Origin of Health and Disease (DOHaD) concept, maternal obesity and accelerated growth in neonates program obesity later in life. White adipose tissue (WAT) has been the focus of developmental programming events, although underlying mechanisms remain elusive. In rodents, WAT development primarily occurs during lactation. We previously reported that adult rat offspring from dams fed a high-fat (HF) diet exhibited fat accumulation and decreased peroxisome proliferator-activated receptor γ (PPARγ) mRNA levels in WAT. We hypothesized that PPARγ down-regulation occurs via epigenetic malprogramming which takes place during adipogenesis. We therefore examined epigenetic modifications in the PPARγ1 and PPARγ2 promoters in perirenal (pWAT) and inguinal fat pads of HF offspring at weaning (postnatal d 21) and in adulthood. Postnatal d 21 is a period characterized by active epigenomic remodeling in the PPARγ2 promoter (DNA hypermethylation and depletion in active histone modification H3ac and H3K4me3) in pWAT, consistent with increased DNA methyltransferase and DNA methylation activities. Adult HF offspring exhibited sustained hypermethylation and histone modification H3ac of the PPARγ2 promoter in both deposits, correlated with persistent decreased PPARγ2 mRNA levels. Consistent with the DOHaD hypothesis, retained epigenetic marks provide a mechanistic basis for the cellular memory linking maternal obesity to a predisposition for later adiposity.-Lecoutre, S., Pourpe, C., Butruille, L., Marousez, L., Laborie, C., Guinez, C., Lesage, J., Vieau, D., Eeckhoute, J., Gabory, A., Oger, F., Eberlé, D., Breton, C. Reduced PPARγ2 expression in adipose tissue of male rat offspring from obese dams is associated with epigenetic modifications.
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http://dx.doi.org/10.1096/fj.201700997RDOI Listing
May 2018

Short-term Impact of Assisted Deliveries: Evaluation Based on Behavioral Pain Scoring and Heart Rate Variability.

Clin J Pain 2018 05;34(5):445-449

Perinatal Environment and Health, Lille medical scool, research department.

Objectives: Assisted deliveries (ADs) are used in current practice by obstetrical teams during labor when the fetus is likely to face difficulties. In this study, we hypothesized that pain related to instrumental delivery could impair autonomic nervous system (ANS) activity.

Materials And Methods: We investigated infants born by spontaneous delivery (SD group, n=35) and those whose deliveries were assisted by vacuum, forceps, or both (AD group, n=35) between the second and fourth hours of life. Pain was evaluated using the Echelle de Douleur et d'Inconfort du Nouveau-Né/Neonatal Pain and Discomfort Scale (EDIN) behavioral pain scale. ANS activity was analyzed using the newborn infant parasympathetic evaluation (NIPE) index, a heart rate variability based index which is related to the autonomic activity mediated by the parasympathetic nervous system.

Results: Neonates in the AD group presented higher EDIN scores than neonates born by spontaneous vaginal deliveries (SD group) (P<0.0001). In contrast, the NIPE index was significantly reduced in the AD group compared with the SD group (P=0.005). A significant inverse correlation was found between the NIPE index and the EDIN score (r=-0.287, P=0.016).

Discussion: ADs (vacuum, forceps, or both) are associated with persistent pain after birth, unlike normal vaginal deliveries. Moreover ADs are associated with reduced NIPE. Taken together, our results suggest that pain related to instrumental delivery impairs the ANS activity.
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http://dx.doi.org/10.1097/AJP.0000000000000572DOI Listing
May 2018

Maternal obesity programs increased leptin gene expression in rat male offspring via epigenetic modifications in a depot-specific manner.

Mol Metab 2017 08 31;6(8):922-930. Epub 2017 May 31.

Univ. Lille, EA4489, Équipe Malnutrition Maternelle et Programmation des Maladies Métaboliques, F-59000 Lille, France. Electronic address:

Objective: According to the Developmental Origin of Health and Disease (DOHaD) concept, maternal obesity and accelerated growth in neonates predispose offspring to white adipose tissue (WAT) accumulation. In rodents, adipogenesis mainly develops during lactation. The mechanisms underlying the phenomenon known as developmental programming remain elusive. We previously reported that adult rat offspring from high-fat diet-fed dams (called HF) exhibited hypertrophic adipocyte, hyperleptinemia and increased leptin mRNA levels in a depot-specific manner. We hypothesized that leptin upregulation occurs via epigenetic malprogramming, which takes place early during development of WAT.

Methods: As a first step, we identified two potential enhancers located upstream and downstream of the leptin transcription start site that exhibit strong dynamic epigenomic remodeling during adipocyte differentiation. We then focused on epigenetic modifications (methylation, hydroxymethylation, and histone modifications) of the promoter and the two potential enhancers regulating leptin gene expression in perirenal (pWAT) and inguinal (iWAT) fat pads of HF offspring during lactation (postnatal days 12 (PND12) and 21 (PND21)) and in adulthood.

Results: PND12 is an active period for epigenomic remodeling in both deposits especially in the upstream enhancer, consistent with leptin gene induction during adipogenesis. Unlike iWAT, some of these epigenetic marks were still observable in pWAT of weaned HF offspring. Retained marks were only visible in pWAT of 9-month-old HF rats that showed a persistent "expandable" phenotype.

Conclusions: Consistent with the DOHaD hypothesis, persistent epigenetic remodeling occurs at regulatory regions especially within intergenic sequences, linked to higher leptin gene expression in adult HF offspring in a depot-specific manner.
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http://dx.doi.org/10.1016/j.molmet.2017.05.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5518658PMC
August 2017

Fetal Heart-Rate Variability: Validation of a New Continuous, Noninvasive Computerized Analysis.

Gynecol Obstet Invest 2017 14;82(5):500-507. Epub 2016 Dec 14.

Univ. Lille, EA 4489 - Environnement Périnatal et Croissance, CHRU de Lille, Lille, France.

Objective: We developed a computerized heart-rate variability index related to the fetal parasympathetic activity: the Fetal Stress Index (FSI). The objective was to determine whether the FSI is related to the visual analysis of the fetal heart rate (FHR).

Methods: Thirty tracings recorded at a labor ward were classified according to the NICHD categories: (I) normal FHR tracing, (II) intermediate risk of acidosis, and (III) high risk. FSI was calculated as minimum, maximum, and mean, and was evaluated before the onset of the FHR pattern, during the 10 min following, and between 10 and 20 min after that.

Results: The FSI for categories II and III was similar to that of category I before the onset of the FHR pattern. FSI min was lower just after the onset of the abnormal FHR in category III, compared with that of category I (33 vs. 43, p < 0.001). Between 10 and 20 min after the onset of the abnormal FHR, we observed a significant reduction in FSI min in categories II and III (44 vs. 39 vs. 29.7, p < 0.0001).

Conclusion: Although further studies are necessary for the sake of clinical validation, FSI could constitute an interesting method for the evaluation of fetal well-being.
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http://dx.doi.org/10.1159/000452668DOI Listing
June 2018

[Analysing heart rate variability to improve the monitoring of pain].

Rev Infirm 2016 Dec;65(226):38-39

CHU de Lille, 2, avenue Oscar-Lambret, 59000 Lille, France. Electronic address:

An innovative technique based on the analysis of instantaneous heart rate variability helps to improve the prevention and management of pain and discomfort. Simple to implement, this non-invasive technique is based on the continuous recording of the electrocardiograph signal.
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http://dx.doi.org/10.1016/j.revinf.2016.09.014DOI Listing
December 2016

Parasympathetic tone variations according to umbilical cord pH at birth: a computerized fetal heart rate variability analysis.

J Clin Monit Comput 2017 Dec 15;31(6):1197-1202. Epub 2016 Nov 15.

Maison Régionale de la Recherche Clinique, INSERM CIC-IT 1403, Lille, France.

Non-reassuring fetal heart rate tracings reflect an imbalance between the parasympathetic and sympathetic nervous systems. In this situation, fetal asphyxia can be suspected and may be confirmed by metabolic measurements at birth like low pH or high base deficit values. The objective of this study was to determine whether fetal asphyxia during labor is related to parasympathetic nervous system activity. This is a retrospective study of a database collected in 5 centers. Two hundred and ninety-nine fetal heart rate tracings collected during labor were analyzed. Autonomic nervous system, especially the parasympathetic nervous system, was analyzed using an original index: the FSI (Fetal Stress Index). The FSI is a parasympathetic activity evaluation based on fetal heart rate variability analysis. Infants were grouped based on normal or low pH value at birth. FSI was measured during the last 30 min of labor before birth and compared between groups. The minimum value of the FSI during the last 30 min before delivery was significantly lower in the group with the lower umbilical cord arterial pH value. In this pilot study during labor, FSI was lower in the group of infants with low arterial pH at birth.
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http://dx.doi.org/10.1007/s10877-016-9957-yDOI Listing
December 2017

Maternal obesity alters the apelinergic system at the feto-maternal interface.

Placenta 2016 Mar 12;39:41-4. Epub 2016 Jan 12.

University of Lille 1, EA 4489, Villeneuve d'Ascq, France. Electronic address:

Apelin and its receptor APJ have been implicated in pathologies including cardiovascular disease, diabetes and obesity. Little is known about the function of the apelinergic system during gestation. We evaluated in mice this system at the feto-maternal interface in insulin-resistant obese female (HF) mice. Maternal apelinemia was decreased at term and fetal apelinemia was sixfold higher than maternal level. Ex-vivo, the placenta releases apelin at E12.5 and E18.5. In HF pregnant mice at term, apelinemia as well as placental apelin and APJ mRNA levels were increased whereas placental release of apelin was drastically reduced compared to controls.
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http://dx.doi.org/10.1016/j.placenta.2016.01.006DOI Listing
March 2016

Apelin Controls Fetal and Neonatal Glucose Homeostasis and Is Altered by Maternal Undernutrition.

Diabetes 2016 Mar 2;65(3):554-60. Epub 2015 Dec 2.

Unité Environnement Périnatal et Santé, Equipe d'accueil 4489, Équipe Malnutrition Maternelle et Programmation des Maladies Métaboliques, Université de Lille, Villeneuve d'Ascq, France

The adequate control of glucose homeostasis during both gestation and early postnatal life is crucial for the development of the fetoplacental unit and adaptive physiological responses at birth. Growing evidences indicate that apelin and its receptor, APJ, which are expressed across a wide range of tissues, exert important roles in glucose homeostasis in adults. However, little is known about the function of the apelinergic system during gestation. In this study, we evaluated the activity of this system in rats, the role of apelin in fetal and neonatal glucose homeostasis, and its modulation by maternal food restriction. We found that 1) the apelinergic system was expressed at the fetoplacental interface and in numerous fetal tissues, 2) ex vivo, the placenta released high amounts of apelin in late gestation, 3) intravenous apelin injection in mothers increased the transplacental transport of glucose, and 4) intraperitoneal apelin administration in neonates increased glucose uptake in lung and muscle. Maternal food restriction drastically reduced apelinemia in both mothers and growth-restricted fetuses and altered the expression of the apelinergic system at the fetoplacental interface. Together, our data demonstrate that apelin controls fetal and neonatal glucose homeostasis and is altered by fetal growth restriction induced by maternal undernutrition.
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http://dx.doi.org/10.2337/db15-0228DOI Listing
March 2016

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

Int J Mol Sci 2015 Sep 14;16(9):22081-93. Epub 2015 Sep 14.

EA 4489 Environnement Périnatal et Santé, Pôle Recherche Faculté de Médecine, Université Lille Nord de France, Lille 59045, France.

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.
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http://dx.doi.org/10.3390/ijms160922081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613298PMC
September 2015

Effect of two models of intrauterine growth restriction on alveolarization in rat lungs: morphometric and gene expression analysis.

PLoS One 2013 21;8(11):e78326. Epub 2013 Nov 21.

Institut National de la Santé Et de la Recherche Médicale (INSERM) U767, Paris, France ; PremUp, Paris, France ; Service de Médecine et Réanimation néonatales de Port-Royal, Groupe hospitalier Cochin, Broca, Hôtel-Dieu, Assistance Publique - Hôpitaux de Paris, Paris, France ; Université Paris Descartes, Paris, France.

Intrauterine growth restriction (IUGR) in preterm infants increases the risk of bronchopulmonary dysplasia, characterized by arrested alveolarization. We evaluated the impact of two different rat models (nitric oxide synthase inhibition or protein deprivation) of IUGR on alveolarization, before, during, and at the end of this postnatal process. We studied IUGR rat pups of dams fed either a low protein (LPD) or a normal diet throughout gestation and pups of dams treated by continuous infusion of Nω-nitro-L-arginine methyl ester (L-NAME) or its diluent on the last four days of gestation. Morphometric parameters, alveolar surface (Svap), mean linear intercept (MLI) and radial alveolar count (RAC) and transcriptomic analysis were determined with special focus on genes involved in alveolarization. IUGR pups regained normal weight at day 21 in the two treated groups. In the LPD group, Svap, MLI and RAC were not different from those of controls at day 4, but were significantly decreased at day 21, indicating alveolarization arrest. In the L-NAME group, Svap and RAC were significantly decreased and MLI was increased at day 4 with complete correction at day 21. In the L-NAME model, several factors involved in alveolarization, VEGF, VEGF-R1 and -R2, MMP14, MMP16, FGFR3 and 4, FGF18 and 7, were significantly decreased at day 4 and/or day 10, while the various factors studied were not modified in the LPD group. These results demonstrate that only maternal protein deprivation leads to sustained impairment of alveolarization in rat pups, whereas L-NAME impairs lung development before alveolarization. Known growth factors involved in lung development do not seem to be involved in LPD-induced alveolarization disorders, raising the question of a possible programming of altered alveolarization.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0078326PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836790PMC
September 2014

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

Peptides 2013 Aug 5;46:94-101. Epub 2013 Jun 5.

Unité Environnement Périnatal et Croissance, EA 4489, Faculté de Médecine, Université Lille Nord de France, Pôle Recherche, IFR 114, 59045 Lille, France.

It 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.
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http://dx.doi.org/10.1016/j.peptides.2013.05.013DOI Listing
August 2013

The hypothalamic POMC mRNA expression is upregulated in prenatally undernourished male rat offspring under high-fat diet.

Peptides 2013 May 20;43:146-54. Epub 2013 Mar 20.

Unité Environnement Périnatal et Croissance, UPRES EA 4489, Equipe Dénutritions Maternelles Périnatales, Université Lille-Nord de France, Villeneuve d'Ascq, France.

Epidemiological studies demonstrated that adverse environmental factors leading to intrauterine growth retardation (IUGR) and low birth weight may predispose individuals to increased risk of metabolic syndrome. In rats, we previously demonstrated that adult male IUGR offspring from prenatal 70% food-restricted dams throughout gestation (FR30) were predisposed to energy balance dysfunctions such as impaired glucose intolerance, hyperleptinemia, hyperphagia and adiposity. We investigated whether postweaning moderate high-fat (HF) diet would amplify the phenotype focusing on the hypothalamus gene expression profile. Prenatally undernourished rat offspring were HF-fed from weaning until adulthood while body weight and food intake were measured. Tissue weights, glucose tolerance and plasma endocrine parameters levels were determined in 4-month-old rats. Hypothalamic gene expression profiling of adult FR30 rat was performed using Illumina microarray analysis and the RatRef-12 Expression BeadChip that contains 21,792 rat genes. Under HF diet, contrary to C animals, FR30 rats displayed increased body weight. However, most of the endocrine disorders observed in chow diet-fed adult FR30 were alleviated. We also observed very few gene expression changes in hypothalamus of FR30 rat. Amongst factors involved in hypothalamic energy homeostasis programming system, only the POMC and transthyretin mRNA expression levels were preferentially increased under HF diet. Both elevated gene expression levels may be seen as adaptive mechanisms counteracting against deleterious effects of HF feeding in FR30 animals. This study shows that the POMC gene expression is a key target of long-term developmental programming in prenatally undernourished male rat offspring, specifically within an obesogenic environment.
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http://dx.doi.org/10.1016/j.peptides.2013.03.013DOI Listing
May 2013

Maternal hypertension induced by NO blockade does not program adult metabolic diseases in growth-restricted rat fetuses.

Metabolism 2013 Mar 30;62(3):442-5. Epub 2012 Oct 30.

Université Lille Nord de France, Unité Environnement Périnatal et Croissance, EA 4489, Faculté de Médecine, Pôle Recherche, IFR 114, 59045 Lille.

Objective: Preeclampsia is a frequent and potentially lethal placental insufficiency pathology causing maternal hypertension and proteinuria, as well as a high rate of intrauterine growth retardation (IUGR) in offspring. Reduced nitric oxide (NO) production may play a role in the mechanisms of this disease. As exposure to adverse early life environment and IUGR has been proposed to increase cardiometabolic diseases risk, we investigated in rats the effects of maternal NO blockade on growth and metabolic phenotype of offspring.

Material And Methods: Osmotic pumps were implanted in pregnant rats at E17 and diffused saline or L-NAME (50mg/day), a nitric oxide synthesis inhibitor. At birth, IUGR male newborns without limb defects were selected. Body growth, feeding behavior and glucose tolerance were evaluated in offspring. Organs weights, plasma level of several metabolic hormones and genes expressions were determined in fasted 9month-old rats.

Results: L-NAME mothers had elevated blood pressure at E20. Male offspring from L-NAME mothers had a markedly reduced birth weight and developed postnatal catch-up growth during lactation. Some L-NAME newborns presented some limb defects but were not selected in this study (1/3 of all pups). Improved glucose tolerance and hyperphagia after fasting were found in 3-month-old L-NAME rat but not thereafter. In 9-month-old L-NAME rats, a moderate increase of food intake during the light phase and, after fasting, an augmentation of plasma insulin and a reduction of brown adipose tissue (BAT) deposit were found associated with an increased expression of UCP-1 mRNA in this tissue.

Conclusions: Despite IUGR and postnatal catch up growth, male rats exposed to L-NAME did not develop metabolic diseases when limb defects were not induced by L-NAME. We postulate that maternal hypertension during late gestation is not a major 'programming' metabolic factor for offspring.
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http://dx.doi.org/10.1016/j.metabol.2012.09.006DOI Listing
March 2013

Prenatal fasudil exposure alleviates fetal growth but programs hyperphagia and overweight in the adult male rat.

Eur J Pharmacol 2012 Aug 7;689(1-3):278-84. Epub 2012 Jun 7.

Univ Lille Nord de France, Unité Environnement Périnatal et Croissance, EA 4489, Faculté de Médecine, Pôle Recherche, Bâtiment SN4, Villeneuve d'Ascq, IFR 114, 59045 Lille, France.

Numerous data indicate that Rho kinase inhibitors, such as Fasudil, may constitute a novel therapy for cardiovascular and metabolic diseases. We evaluated long-term effects of exposure to Fasudil during late gestation (10 mg/day) in male rat offspring from birth until 9 months. We also analyzed its effects in offspring from hypertensive mothers treated with a nitric oxide synthesis inhibitor (L-NAME; 50 mg/day). Prenatal exposure to Fasudil did not affect birth weight, but increased body weight from postnatal day 7 (P7) to 9 months. In intrauterine growth-restricted (IUGR) fetuses exposed to L-NAME, maternal Fasudil treatment increased birth weight. At P42 and P180, rats exposed to Fasudil and L-NAME showed alterations of their food intake as well as an increased basal glycemia associated with mild glucose intolerance at 6 months which was also observed in Fasudil-exposed rats. In 9 month-old rats, exposure to Fasudil increased the daily food intake as well as hypothalamic mRNA level of the orexigenic NPY peptide without modulation of the anorexigenic POMC gene expression. Altogether, our data suggest that prenatal Fasudil exposure alleviates fetal growth in IUGR rats, but programs long-term metabolic disturbances including transient perturbations of glucose metabolism, a persistent increase of body weight gain, hyperphagia and an augmented expression of hypothalamic NPY orexigenic gene. We postulate that Fasudil treatment during perinatal periods may predispose individuals to the development of metabolic disorders.
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http://dx.doi.org/10.1016/j.ejphar.2012.05.040DOI Listing
August 2012

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

Peptides 2012 May 15;35(1):136-8. Epub 2012 Mar 15.

Univ Lille Nord de France, Unité Environnement Périnatal et Croissance, EA 4489, Equipe dénutritions maternelles périnatales, Université de Lille 1, Bâtiment SN4, F-59655 Villeneuve d'Ascq, France.

Apelin 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.
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http://dx.doi.org/10.1016/j.peptides.2012.03.005DOI Listing
May 2012
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