Publications by authors named "Fabien Delahaye"

20 Publications

  • Page 1 of 1

Prenatal Hyperglycemia Exposure and Cellular Stress, a Sugar-Coated View of Early Programming of Metabolic Diseases.

Biomolecules 2020 09 23;10(10). Epub 2020 Sep 23.

Institut Pasteur de Lille, U1283-UMR 8199 EGID, Université de Lille, Inserm, CNRS, CHU Lille, F-59000 Lille,

Worldwide, the number of people with diabetes has quadrupled since 1980 reaching 422 million in 2014 (World Health Organization). This distressing rise in diabetes also affects pregnant women and thus, in regard to early programming of adult diseases, creates a vicious cycle of metabolic dysfunction passed from one generation to another. Metabolic diseases are complex and caused by the interplay between genetic and environmental factors. High-glucose exposure during in utero development, as observed with gestational diabetes mellitus (GDM), is an established risk factor for metabolic diseases. Despite intense efforts to better understand this phenomenon of early memory little is known about the molecular mechanisms associating early exposure to long-term diseases risk. However, evidence promotes glucose associated oxidative stress as one of the molecular mechanisms able to influence susceptibility to metabolic diseases. Thus, we decided here to further explore the relationship between early glucose exposure and cellular stress in the context of early development, and focus on the concept of glycemic memory, its consequences, and sexual dimorphic and epigenetic aspects.
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http://dx.doi.org/10.3390/biom10101359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598660PMC
September 2020

DNA methylation loci in placenta associated with birthweight and expression of genes relevant for early development and adult diseases.

Clin Epigenetics 2020 06 3;12(1):78. Epub 2020 Jun 3.

Department of Obstetrics and Gynecology, Columbia University, New York, NY, USA.

Background: Birthweight marks an important milestone of health across the lifespan, including cardiometabolic disease risk in later life. The placenta, a transient organ at the maternal-fetal interface, regulates fetal growth. Identifying genetic loci where DNA methylation in placenta is associated with birthweight can unravel genomic pathways that are dysregulated in aberrant fetal growth and cardiometabolic diseases in later life.

Results: We performed placental epigenome-wide association study (EWAS) of birthweight in an ethnic diverse cohort of pregnant women (n = 301). Methylation at 15 cytosine-(phosphate)-guanine sites (CpGs) was associated with birthweight (false discovery rate (FDR) < 0.05). Methylation at four (26.7%) CpG sites was associated with placental transcript levels of 15 genes (FDR < 0.05), including genes known to be associated with adult lipid traits, inflammation and oxidative stress. Increased methylation at cg06155341 was associated with higher birthweight and lower FOSL1 expression, and lower FOSL1 expression was correlated with higher birthweight. Given the role of the FOSL1 transcription factor in regulating developmental processes at the maternal-fetal interface, epigenetic mechanisms at this locus may regulate fetal development. We demonstrated trans-tissue portability of methylation at four genes (MLLT1, PDE9A, ASAP2, and SLC20A2) implicated in birthweight by a previous study in cord blood. We also found that methylation changes known to be related to maternal underweight, preeclampsia and adult type 2 diabetes were associated with lower birthweight in placenta.

Conclusion: We identified novel placental DNA methylation changes associated with birthweight. Placental epigenetic mechanisms may underlie dysregulated fetal development and early origins of adult cardiometabolic diseases.

Clinical Trial Registration: ClinicalTrials.gov, NCT00912132.
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http://dx.doi.org/10.1186/s13148-020-00873-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268466PMC
June 2020

Retargeting of macroH2A following mitosis to cytogenetic-scale heterochromatic domains.

J Cell Biol 2019 06 20;218(6):1810-1823. Epub 2019 May 20.

Center for Epigenomics and Department of Genetics, Albert Einstein College of Medicine, Bronx, NY

The heritability of chromatin states through cell division is a potential contributor to the epigenetic maintenance of cellular memory of prior states. The macroH2A histone variant has properties of a regulator of epigenetic cell memory, including roles controlling gene silencing and cell differentiation. Its mechanisms of regional genomic targeting and maintenance through cell division are unknown. Here, we combined in vivo imaging with biochemical and genomic approaches to show that human macroH2A is incorporated into chromatin in the G1 phase of the cell cycle following DNA replication. The newly incorporated macroH2A retargets the same large heterochromatic domains where macroH2A was already enriched in the previous cell cycle. It remains heterotypic, targeting individual nucleosomes that do not already contain a macroH2A molecule. The pattern observed resembles that of a new deposition of centromeric histone variants during the cell cycle, indicating mechanistic similarities for macrodomain-scale regulation of epigenetic properties of the cell.
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http://dx.doi.org/10.1083/jcb.201811109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548134PMC
June 2019

Genetic variants influence on the placenta regulatory landscape.

PLoS Genet 2018 11 19;14(11):e1007785. Epub 2018 Nov 19.

Department of Obstetrics and Gynecology, NYU Langone Health, New York, New York, United States of America.

From genomic association studies, quantitative trait loci analysis, and epigenomic mapping, it is evident that significant efforts are necessary to define genetic-epigenetic interactions and understand their role in disease susceptibility and progression. For this reason, an analysis of the effects of genetic variation on gene expression and DNA methylation in human placentas at high resolution and whole-genome coverage will have multiple mechanistic and practical implications. By producing and analyzing DNA sequence variation (n = 303), DNA methylation (n = 303) and mRNA expression data (n = 80) from placentas from healthy women, we investigate the regulatory landscape of the human placenta and offer analytical approaches to integrate different types of genomic data and address some potential limitations of current platforms. We distinguish two profiles of interaction between expression and DNA methylation, revealing linear or bimodal effects, reflecting differences in genomic context, transcription factor recruitment, and possibly cell subpopulations. These findings help to clarify the interactions of genetic, epigenetic, and transcriptional regulatory mechanisms in normal human placentas. They also provide strong evidence for genotype-driven modifications of transcription and DNA methylation in normal placentas. In addition to these mechanistic implications, the data and analytical methods presented here will improve the interpretability of genome-wide and epigenome-wide association studies for human traits and diseases that involve placental functions.
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http://dx.doi.org/10.1371/journal.pgen.1007785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277118PMC
November 2018

Effect of diet in females (F1) from prenatally undernourished mothers on metabolism and liver function in the F2 progeny is sex-specific.

Eur J Nutr 2019 Sep 30;58(6):2411-2423. Epub 2018 Aug 30.

Division of Maternal Malnutrition, Department of Perinatal Environment and Health, Lille University, Lille, France.

Purpose: Poor maternal nutrition sensitises to the development of metabolic diseases and obesity in adulthood over several generations. The prevalence increases when offspring is fed with a high-fat (HF) diet after weaning. This study aims to determine whether such metabolic profiles can be transmitted to the second generation and even aggravated when the mothers were exposed to overnutrition, with attention to potential sex differences.

Methods: Pregnant Wistar rats were subjected to ad libitum (control) or 70% food-restricted diet (FR) during gestation (F0). At weaning, F1 females were allocated to three food protocols: (1) standard diet prior to and throughout gestation and lactation, (2) HF diet prior to and standard diet throughout gestation and lactation, and (3) HF diet prior to and throughout gestation and lactation. F2 offspring was studied between 16 and 32 weeks of age.

Results: FR-F2 offspring on standard diet showed normal adiposity and had no significant metabolic alterations in adulthood. Maternal HF diet resulted in sex-specific effects with metabolic disturbances more apparent in control offspring exposed to HF diet during gestation and lactation. Control offspring displayed glucose intolerance associated with insulin resistance in females. Female livers overexpressed lipogenesis genes and those of males the genes involved in lipid oxidation. Gene expression was significantly attenuated in the FR livers. Increased physical activity associated with elevated corticosterone levels was observed in FR females on standard diet and in all females from overnourished mothers.

Conclusions: Maternal undernutrition during gestation (F0) improves the metabolic health of second-generation offspring with more beneficial effects in females.
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http://dx.doi.org/10.1007/s00394-018-1794-yDOI Listing
September 2019

Late-life targeting of the IGF-1 receptor improves healthspan and lifespan in female mice.

Nat Commun 2018 06 19;9(1):2394. Epub 2018 Jun 19.

Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.

Diminished growth factor signaling improves longevity in laboratory models, while a reduction in the somatotropic axis is favorably linked to human aging and longevity. Given the conserved role of this pathway on lifespan, therapeutic strategies, such as insulin-like growth factor-1 receptor (IGF-1R) monoclonal antibodies (mAb), represent a promising translational tool to target human aging. To this end, we performed a preclinical study in 18-mo-old male and female mice treated with vehicle or an IGF-1R mAb (L2-Cmu, Amgen Inc), and determined effects on aging outcomes. Here we show that L2-Cmu preferentially improves female healthspan and increases median lifespan by 9% (P = 0.03) in females, along with a reduction in neoplasms and inflammation (P ≤ 0.05). Thus, consistent with other models, targeting IGF-1R signaling appears to be most beneficial to females. Importantly, these effects could be achieved at advanced ages, suggesting that IGF-1R mAbs could represent a promising therapeutic candidate to delay aging.
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http://dx.doi.org/10.1038/s41467-018-04805-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008442PMC
June 2018

Intrauterine Hyperglycemia Is Associated with an Impaired Postnatal Response to Oxidative Damage.

Stem Cells Dev 2018 05 26;27(10):683-691. Epub 2018 Apr 26.

5 Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, NYU Langone Medical Center , New York, New York.

Hyperglycemia and other adverse exposures early in life that reprogram stem cells may lead to long-lasting phenotypic influences over the lifetime of an individual. Hyperglycemia and oxidative stress cause DNA damage when they exceed the protective capabilities of the cell, in turn affecting cellular function. DNA damage in response to hyperglycemia and oxidative stress was studied in human umbilical cord mesenchymal stem cells (hUC-MSCs) from large-for-gestational-age (LGA) infants of mothers with gestational diabetes mellitus (LGA-GDM) and control subjects. We tested the response of these cells to hyperglycemia and oxidative stress, measuring reactive oxygen species (ROS) levels and antioxidant enzyme activities. We find that hUC-MSCs from LGA-GDM infants have increased DNA damage when exposed to oxidative stress. With the addition of hyperglycemic conditions, these cells have an increase in ROS and a decrease in antioxidant glutathione peroxidase (GPx) activity, indicating a mechanism for the increased ROS and DNA damage. This study demonstrates that a memory of in utero hyperglycemia, mediated through downregulation of GPx activity, leads to an increased susceptibility to oxidative stress. The alteration of GPx function in self-renewing stem cells, can mediate the effect of intrauterine hyperglycemia to be propagated into adulthood and contribute to disease susceptibility.
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http://dx.doi.org/10.1089/scd.2017.0232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5962324PMC
May 2018

inactivation, but not obesity, synergizes with deficiency to drive intestinal stem cell-derived tumorigenesis.

Endocr Relat Cancer 2017 06 28;24(6):253-265. Epub 2017 Mar 28.

Department of Molecular PharmacologyAlbert Einstein College of Medicine, Bronx, New York, USA

Obesity is a major risk factor for colorectal cancer and can accelerate Lgr5+ intestinal stem cell (ISC)-derived tumorigenesis after the inactivation of However, whether non-canonical pathways involving PI3K-Akt signaling in ISCs can lead to tumor formation, and if this can be further exacerbated by obesity is unknown. Despite the synergy between and inactivation in epithelial cells on intestinal tumor formation, their combined role in Lgr5+-ISCs, which are the most rapidly dividing ISC population in the intestine, is unknown. Lgr5+-GFP mice were provided low-fat diet (LFD) or high-fat diet (HFD) for 8 months, and the transcriptome was evaluated in Lgr5+-ISCs. For tumor studies, Lgr5+-GFP and Lgr5+-GFP- mice were tamoxifen treated to inactivate in ISCs and provided LFD or HFD until 14-15 months of age. Finally, various combinations of Lgr5+-ISC-specific, and -deleted mice were generated and evaluated for histopathology and survival. HFD did not overtly alter Akt signaling in ISCs, but did increase other metabolic pathways. deficiency, but not HFD, increased BrdU-positive cells in the small intestine ( < 0.05). However, combining and deficiency synergistically increased proliferative markers, tumor pathology and mortality, in a dose-dependent fashion ( < 0.05). In summary, we show that HFD alone fails to drive Akt signaling in ISCs and that deficiency is dispensable as a tumor suppressor in Lgr5+-ISCs. However, combining and deficiency in ISCs synergistically increases proliferation, tumor formation and mortality. Thus, aberrant Wnt/β-catenin, rather than PI3K-Akt signaling, is requisite for obesity to drive Lgr5+ ISC-derived tumorigenesis.
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http://dx.doi.org/10.1530/ERC-16-0536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5505256PMC
June 2017

SMITE: an R/Bioconductor package that identifies network modules by integrating genomic and epigenomic information.

BMC Bioinformatics 2017 Jan 18;18(1):41. Epub 2017 Jan 18.

Department of Genetics, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY, 10461, USA.

Background: The molecular assays that test gene expression, transcriptional, and epigenetic regulation are increasingly diverse and numerous. The information generated by each type of assay individually gives an insight into the state of the cells tested. What should be possible is to add the information derived from separate, complementary assays to gain higher-confidence insights into cellular states. At present, the analysis of multi-dimensional, massive genome-wide data requires an initial pruning step to create manageable subsets of observations that are then used for integration, which decreases the sizes of the intersecting data sets and the potential for biological insights. Our Significance-based Modules Integrating the Transcriptome and Epigenome (SMITE) approach was developed to integrate transcriptional and epigenetic regulatory data without a loss of resolution.

Results: SMITE combines p-values by accounting for the correlation between non-independent values within data sets, allowing genes and gene modules in an interaction network to be assigned significance values. The contribution of each type of genomic data can be weighted, permitting integration of individually under-powered data sets, increasing the overall ability to detect effects within modules of genes. We apply SMITE to a complex genomic data set including the epigenomic and transcriptomic effects of Toxoplasma gondii infection on human host cells and demonstrate that SMITE is able to identify novel subnetworks of dysregulated genes. Additionally, we show that SMITE outperforms Functional Epigenetic Modules (FEM), the current paradigm of using the spin-glass algorithm to integrate gene expression and epigenetic data.

Conclusions: SMITE represents a flexible, scalable tool that allows integration of transcriptional and epigenetic regulatory data from genome-wide assays to boost confidence in finding gene modules reflecting altered cellular states.
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http://dx.doi.org/10.1186/s12859-017-1477-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5242055PMC
January 2017

Advanced aging phenotype is revealed by epigenetic modifications in rat liver after in utero malnutrition.

Aging Cell 2016 10 29;15(5):964-72. Epub 2016 Jul 29.

Department of Obstetrics & Gynecology and Women's Health, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY, 10461, USA.

Adverse environmental exposures of mothers during fetal period predispose offspring to a range of age-related diseases earlier in life. Here, we set to determine whether a deregulated epigenetic pattern is similar in young animals whose mothers' nutrition was modulated during fetal growth to that acquired during normal aging in animals. Using a rodent model of maternal undernutrition (UN) or overnutrition (ON), we examined cytosine methylation profiles of liver from young female offspring and compared them to age-matched young controls and aged (20-month-old) animals. HELP-tagging, a genomewide restriction enzyme and sequencing assay demonstrates that fetal exposure to two different maternal diets is associated with nonrandom dysregulation of methylation levels with profiles similar to those seen in normal aging animals and occur in regions mapped to genes relevant to metabolic diseases and aging. Functional consequences were assessed by gene expression at 9 weeks old with more significant changes at 6 months of age. Early developmental exposures to unfavorable maternal diets result in altered methylation profiles and transcriptional dysregulation in Prkcb, Pc, Ncor2, and Smad3 that is also seen with normal aging. These Notch pathway and lipogenesis genes may be useful for prediction of later susceptibility to chronic disease.
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http://dx.doi.org/10.1111/acel.12505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5013021PMC
October 2016

DNA hypermethylation of CD3(+) T cells from cord blood of infants exposed to intrauterine growth restriction.

Diabetologia 2016 08 17;59(8):1714-23. Epub 2016 May 17.

Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Rm F312, Bronx, NY, 10461, USA.

Aims/hypothesis: Intrauterine growth restriction (IUGR) is associated with increased susceptibility to obesity, metabolic syndrome and type 2 diabetes. Although the mechanisms underlying the developmental origins of metabolic disease are poorly understood, evidence suggests that epigenomic alterations play a critical role. We sought to identify changes in DNA methylation patterns that are associated with IUGR in CD3(+) T cells purified from umbilical cord blood obtained from male newborns who were appropriate for gestational age (AGA) or who had been exposed to IUGR.

Methods: CD3(+) T cells were isolated from cord blood obtained from IUGR and AGA infants. The genome-wide methylation profile in eight AGA and seven IUGR samples was determined using the HELP tagging assay. Validation analysis using targeted bisulfite sequencing and bisulfite massARRAY was performed on the original cohort as well as biological replicates consisting of two AGA and four IUGR infants. The Segway algorithm was used to identify methylation changes within regulatory regions of the genome.

Results: A global shift towards hypermethylation in IUGR was seen compared with AGA (89.8% of 4,425 differentially methylated loci), targeted to regulatory regions of the genome, specifically promoters and enhancers. Pathway analysis identified dysregulation of pathways involved in metabolic disease (type 2 diabetes mellitus, insulin signalling, mitogen-activated protein kinase signalling) and T cell development, regulation and activation (T cell receptor signalling), as well as transcription factors (TCF3, LEF1 and NFATC) that regulate T cells. Furthermore, bump-hunting analysis revealed differentially methylated regions in PRDM16 and HLA-DPB1, genes important for adipose tissue differentiation, stem cell maintenance and function and T cell activation.

Conclusions/interpretation: Our findings suggest that the alterations in methylation patterns observed in IUGR CD3(+) T cells may have functional consequences in targeted genes, regulatory regions and transcription factors. These may serve as biomarkers to identify those at 'high risk' for diminished attainment of full health potential who can benefit from early interventions.

Access To Research Materials: HELP tagging data: Gene Expression Omnibus database (GSE77268), scheduled to be released on 25 January 2019.
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http://dx.doi.org/10.1007/s00125-016-3983-7DOI Listing
August 2016

The meta-epigenomic structure of purified human stem cell populations is defined at cis-regulatory sequences.

Nat Commun 2014 Oct 20;5:5195. Epub 2014 Oct 20.

Center for Epigenomics and Department of Genetics (Division of Computational Genetics), Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY 10461, USA.

The mechanism and significance of epigenetic variability in the same cell type between healthy individuals are not clear. Here we purify human CD34+ haematopoietic stem and progenitor cells (HSPCs) from different individuals and find that there is increased variability of DNA methylation at loci with properties of promoters and enhancers. The variability is especially enriched at candidate enhancers near genes transitioning between silent and expressed states, and encoding proteins with leukocyte differentiation properties. Our findings of increased variability at loci with intermediate DNA methylation values, at candidate 'poised' enhancers and at genes involved in HSPC lineage commitment suggest that CD34+ cell subtype heterogeneity between individuals is a major mechanism for the variability observed. Epigenomic studies performed on cell populations, even when purified, are testing collections of epigenomes, or meta-epigenomes. Our findings show that meta-epigenomic approaches to data analysis can provide insights into cell subpopulation structure.
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http://dx.doi.org/10.1038/ncomms6195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4300104PMC
October 2014

Sexual dimorphism in epigenomic responses of stem cells to extreme fetal growth.

Nat Commun 2014 Oct 10;5:5187. Epub 2014 Oct 10.

Department of Obstetrics &Gynecology and Women's Health, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Block Building, Room 631, Bronx, New York 10461, USA.

Extreme fetal growth is associated with increased susceptibility to a range of adult diseases through an unknown mechanism of cellular memory. We tested whether heritable epigenetic processes in long-lived CD34(+) haematopoietic stem/progenitor cells showed evidence for re-programming associated with the extremes of fetal growth. Here we show that both fetal growth restriction and over-growth are associated with global shifts towards DNA hypermethylation, targeting cis-regulatory elements in proximity to genes involved in glucose homeostasis and stem cell function. We find a sexually dimorphic response; intrauterine growth restriction is associated with substantially greater epigenetic dysregulation in males, whereas large for gestational age growth predominantly affects females. The findings are consistent with extreme fetal growth interacting with variable fetal susceptibility to influence cellular ageing and metabolic characteristics through epigenetic mechanisms, potentially generating biomarkers that could identify infants at higher risk for chronic disease later in life.
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http://dx.doi.org/10.1038/ncomms6187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4197137PMC
October 2014

Is the adipose tissue a key target of developmental programming of adult adiposity by maternal undernutrition?

Adipocyte 2012 Jan;1(1):64-67

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

Epidemiological studies have shown that maternal undernutrition during pregnancy (MU) leads to intrauterine growth retardation and low birth weight, and may predispose individuals to the development of metabolic syndrome symptoms later in life such as overweight. Some clues from a model of prenatal maternal 70% food-restricted diet throughout gestation in pregnant female rats (FR30) suggest that the white adipose tissue (WAT) is a key target of MU fetal programming. Under standard diet, although showing a lean phenotype, adult FR30 male rats were predisposed to adiposity exhibiting higher serum leptin and corticosterone concentration, two hormones actively involved in WAT regulation. Although FR30 procedure does not worsen the metabolic syndrome features induced by HF diet, FR30HF rats gained more weight and showed hyperleptinemia suggesting increased adiposity. WAT FR30 adult rats revealed marked changes in transcript levels of several genes. In particular, leptin and Ob-Rb, many peptide precursors and receptors, factors involved in lipogenesis and glucocorticoid sensitivity mRNA expression levels as well as mechanisms involved in leptin sensitivity, were modified in FR30 offspring in depot-specific and diet-specific manners. These modifications might predispose for altered fat accumulation in adult male rat offspring.
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http://dx.doi.org/10.4161/adip.18952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3661123PMC
January 2012

Maternal prenatal undernutrition programs adipose tissue gene expression in adult male rat offspring under high-fat diet.

Am J Physiol Endocrinol Metab 2011 Sep 28;301(3):E548-59. Epub 2011 Jun 28.

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

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 11β-HSD1, 11β-HSD2, GR, and MR genes are coexpressed in WAT and that FR30 procedure modifies gene expression levels, especially under HF diet. In particular, level variation of 11β-HSD2, whose protein expression was detected by Western blotting, may represent a novel mechanism that may affect WAT glucocorticoid sensitivity. Data suggest that maternal undernutrition differently programs the adult offspring WAT gene expression profile that may predispose for altered fat deposition.
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http://dx.doi.org/10.1152/ajpendo.00011.2011DOI Listing
September 2011

Influence of prenatal undernutrition on the effects of clozapine and aripiprazole in the adult male rats: relevance to a neurodevelopmental origin of schizophrenia?

Eur J Pharmacol 2011 Sep 15;667(1-3):402-9. Epub 2011 Apr 15.

Equipe Dénutritions Maternelles Périnatales (Unité Environnement Périnatal et Croissance, EA4489), Bâtiment SN4, 2(ème) étage, Université des Sciences et Technologies de Lille, Université Lille-Nord de France, 59 655 Villeneuve d'Ascq cedex, France.

Epidemiological and experimental data indicate that maternal undernutrition may sensitize the offspring to the apparition of chronic diseases such as metabolic syndrome and schizophrenia, suggesting that these pathologies may have a developmental origin. To test this hypothesis, we have compared the effects of a 4 weeks treatment of clozapine (30 mg/kg once daily, p.o.) or aripiprazole (10 mg/kg once daily, p.o.) on metabolic and hormonal parameters in 4-month-old male animals from control or 70% prenatally food-restricted mothers (FR30 model). Both neuroleptics did not markedly modify body weight gain and food intake in both controls and FR30 rats. Clozapine decreased insulin secretion in both groups but significantly diminished leptin, corticosterone and glucose plasma levels only in FR30 animals. Aripiprazole decreased corticosterone plasma levels only in FR30 animals. Using quantitative RT-PCR array containing 84 obesity-related genes, we identified several genes involved in energy metabolism regulation whose expression was modified by clozapine or aripiprazole in adult male rat hypothalami. In addition, we demonstrated that expression of some of these genes was differentially affected by each neuroleptic in the hypothalamus of both FR30 and control animals. Although no marked metabolic alterations were observed in both control and FR30 animals after clozapine or aripiprazole treatment, our data indicate that offspring from undernourished mothers exhibit a modified sensitivity to atypical neuroleptics. Our results do not rule out a putative developmental origin of schizophrenia and may help to understand the way by which atypical neuroleptics, such as clozapine, sensitize schizophrenic patients to the development of metabolic disorders.
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http://dx.doi.org/10.1016/j.ejphar.2011.04.011DOI Listing
September 2011

Maternal perinatal undernutrition programs a "brown-like" phenotype of gonadal white fat in male rat at weaning.

Am J Physiol Regul Integr Comp Physiol 2010 Jul 12;299(1):R101-10. Epub 2010 May 12.

Unité Environnement Périnatal et Croissance (EA 4489), Université Lille-Nord de France, Equipe Dénutritions Maternelles Périnatales, Université de Lille 1, Villeneuve d'Ascq, France.

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.
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http://dx.doi.org/10.1152/ajpregu.00604.2009DOI Listing
July 2010

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

Am J Physiol Endocrinol Metab 2009 Mar 16;296(3):E462-72. Epub 2008 Dec 16.

Neurosciences et Physiologie Adaptatives, Université de Lille I, Villeneuve d'Ascq, France.

Epidemiological 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.
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http://dx.doi.org/10.1152/ajpendo.90740.2008DOI Listing
March 2009

Maternal perinatal undernutrition drastically reduces postnatal leptin surge and affects the development of arcuate nucleus proopiomelanocortin neurons in neonatal male rat pups.

Endocrinology 2008 Feb 15;149(2):470-5. Epub 2007 Nov 15.

Unité de Neurosciences et Physiologie Adaptatives, Equipe Associée 4052, Bâtiment SN4, 2ème étage, Université des Sciences et Technologies de Lille, 59655, Villeneuve d'Ascq Cédex, France.

A growing body of evidence suggests that maternal undernutrition sensitizes the offspring to the development of energy balance metabolic disorders such as type 2 diabetes, dyslipidemia, and obesity. The present study aimed at examining the impact of maternal undernutrition on leptin plasma levels in newborn male rats and on the arcuate nucleus proopiomelanocortin (POMC) and neuropeptide Y (NPY) neurons that are major leptin targets. Using a model of perinatal maternal 50% food-restricted diet (FR50) in the rat, we evaluated leptin plasma levels and hypothalamic POMC and NPY gene expression from postnatal day (PND) 4 to PND30 in both control and FR50 offspring. In control rats, a postnatal peak of plasma leptin was observed between PND4 and PND14 that reached a maximal value at PND10 (5.17 +/- 0.53 ng/ml), whereas it was dramatically reduced in FR50 pups with the higher concentration at PND7 (0.93 +/- 0.23 ng/ml). In FR50 animals, using semiquantitative RT-PCR and in situ hybridization, we showed that the hypothalamic POMC mRNA level was decreased from PND14 until PND30, whereas NPY gene expression was not significantly modified. In PND21 FR50 animals, we observed strikingly reduced immunoreactive beta-endorphin nerve fibers projecting to the hypothalamic paraventricular nucleus without affecting NPY projections. Our data showed that maternal undernutrition drastically reduces the postnatal surge of plasma leptin, disturbing particularly the hypothalamic wiring as well as the gene expression of the anorexigenic POMC neurons in male rat pups. These alterations might contribute to the adult metabolic disorders resulting from perinatal growth retardation.
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http://dx.doi.org/10.1210/en.2007-1263DOI Listing
February 2008