Developmental and long-term metabolic and epigenetic memory of preconceptional maternal weight trajectories

L’obésité maternelle peut prédisposer aux pathologies métaboliques à l’âge adulte. Une perte de poids préconceptionnelle est recommandée aux femmes obèses, mais ses effets sur la santé de la descendance sont encore peu connus. Les objectifs de cette thèse ont été d’étudier les effets des trajectoires pondérales maternelles préconceptionnelles sur le phénotype métabolique de la descendance à l’âge adulte et d’aborder les mécanismes épigénétiques sous-jacents à terme de gestation. L’étude s’appuie sur un modèle murin comprenant trois groupes maternels (contrôle, obèse et perte de poids) et deux groupes de descendants (alimentation normale ou riche en lipides). Des analyses multifactorielles ont mis en évidence un effet majeur du sexe et du régime post sevrage sur le phénotype des descendants, ainsi qu’un effet de conditionnement par la physiologie maternelle chez les mâles soumis à un régime hyperlipidique. Une analyse métabolomique du foie, de l’hypothalamus et du bulbe olfactif de descendants mâles adultes, a confirmé l’effet majeur du régime post-sevrage sur plusieurs voies métaboliques, et a permis d’identifier 3 métabolites communs aux trois tissus. De plus, cette étude a révélé un effet de programmation par l’obésité maternelle dans le foie. A terme de gestation, nous avons également démarré une étude préliminaire concernant les modifications post-traductionnelles des histones, en particulier leur acétylation. Ce travail apporte des éléments inédits concernant les acteurs et les mécanismes de la programmation et du conditionnement développemental de la descendance par les trajectoires pondérales maternelles préconceptionnelles.Maternal obesity can predispose to metabolic pathologies in adulthood. Preconceptional weight loss is recommended for obese women, but its effects on the health of the offspring are still poorly understood. The objectives of this thesis were to study the effects of preconceptional maternal weight trajectories on the metabolic phenotype of offspring in adulthood and to address the underlying epigenetic mechanisms at gestation term. The study is based on a mouse model comprising three maternal groups (control, obese and weight loss) and two offspring groups (normal or high-fat diet). Multifactorial analyzes revealed a major effect of sex and post-weaning diet on the phenotype of offspring, as well as a conditioning effect by maternal physiology in males under high-fat diet. A metabolomic analysis of the liver, hypothalamus and olfactory bulb of adult male offspring confirmed the major effect of post-weaning diet on several metabolic pathways, and identified 3 metabolites common to all three tissues. In addition, this study revealed a programming effect by maternal obesity in the liver. At term of gestation, we also started a preliminary study concerning the post-translational modifications of the histones, in particular their acetylation. This work brings novel elements concerning the actors and the mechanisms of the programming and the developmental conditioning of the offspring by the preconceptional maternal weight trajectories

Mémoire métabolique et épigénétique des trajectoires pondérales maternelles préconceptionnelles, au cours du développement et à long terme

Maternal obesity can predispose to metabolic pathologies in adulthood. Preconceptional weight loss is recommended for obese women, but its effects on the health of the offspring are still poorly understood. The objectives of this thesis were to study the effects of preconceptional maternal weight trajectories on the metabolic phenotype of offspring in adulthood and to address the underlying epigenetic mechanisms at gestation term. The study is based on a mouse model comprising three maternal groups (control, obese and weight loss) and two offspring groups (normal or high-fat diet). Multifactorial analyzes revealed a major effect of sex and post-weaning diet on the phenotype of offspring, as well as a conditioning effect by maternal physiology in males under high-fat diet. A metabolomic analysis of the liver, hypothalamus and olfactory bulb of adult male offspring confirmed the major effect of post-weaning diet on several metabolic pathways, and identified 3 metabolites common to all three tissues. In addition, this study revealed a programming effect by maternal obesity in the liver. At term of gestation, we also started a preliminary study concerning the post-translational modifications of the histones, in particular their acetylation. This work brings novel elements concerning the actors and the mechanisms of the programming and the developmental conditioning of the offspring by the preconceptional maternal weight trajectories.L’obésité maternelle peut prédisposer aux pathologies métaboliques à l’âge adulte. Une perte de poids préconceptionnelle est recommandée aux femmes obèses, mais ses effets sur la santé de la descendance sont encore peu connus. Les objectifs de cette thèse ont été d’étudier les effets des trajectoires pondérales maternelles préconceptionnelles sur le phénotype métabolique de la descendance à l’âge adulte et d’aborder les mécanismes épigénétiques sous-jacents à terme de gestation. L’étude s’appuie sur un modèle murin comprenant trois groupes maternels (contrôle, obèse et perte de poids) et deux groupes de descendants (alimentation normale ou riche en lipides). Des analyses multifactorielles ont mis en évidence un effet majeur du sexe et du régime post sevrage sur le phénotype des descendants, ainsi qu’un effet de conditionnement par la physiologie maternelle chez les mâles soumis à un régime hyperlipidique. Une analyse métabolomique du foie, de l’hypothalamus et du bulbe olfactif de descendants mâles adultes, a confirmé l’effet majeur du régime post-sevrage sur plusieurs voies métaboliques, et a permis d’identifier 3 métabolites communs aux trois tissus. De plus, cette étude a révélé un effet de programmation par l’obésité maternelle dans le foie. A terme de gestation, nous avons également démarré une étude préliminaire concernant les modifications post-traductionnelles des histones, en particulier leur acétylation. Ce travail apporte des éléments inédits concernant les acteurs et les mécanismes de la programmation et du conditionnement développemental de la descendance par les trajectoires pondérales maternelles préconceptionnelles

Epigenetics and the Developmental Origins of Health and Disease : Parental environment signalling to the epigenome, critical time windows and sculpting the adult phenotype

The literature about Developmental Origins of Health and Disease (DOHaD) studies is considerably growing. Maternal and paternal environment, during all the development of the individual from gametogenesis to weaning and beyond, as well as the psychosocial environment in childhood and teenage, can shape the adult and the elderly person’s susceptibility to her/his own environment and diseases. This non-conventional, non-genetic, inheritance is underlain by several mechanisms among which epigenetics is obviously central, due to the notion of memory of early decisional events during development even when this stimulus is gone, that is implied in Waddington’s developmental concept. This review first summarizes the different mechanisms by which the environment can model the epigenome: receptor signalling, energy metabolism and signal mechanotransduction from extracellular matrix to chromatin. Then an overview of the epigenetic changes in response to maternal environment during the vulnerability time windows, gametogenesis, early development, placentation and foetal growth, and postnatal period, is described, with the specific example of overnutrition and food deprivation. The implication of epigenetics in DOHaD is obvious, however the precise causal chain from early environment to the epigenome modifications to the phenotype still needs to be deciphered

Effects of preconceptional maternal weight trajectories on offspring health

Since the 90’s, obesity became pandemic. Nutritional environment has an important impact during development, leading to the later onset of non-communicable diseases. Maternal environment may affect offspring development through epigenetic mechanisms, regulating gene expression and microbiota, which is a major actor of metabolism. In order to reduce fertility troubles and obstetrical complications caused by obesity, it is now recommended for women who plan a pregnancy to lose weight before conception. However, the long-term effects of this preconception weight loss are not well described in the literature. We aim to identify whether maternal weight loss prior to conception can prevent the development of metabolic syndrome at the adult age. We previously highlighted in a mouse model the high sensitivity of the epigenetic machinery gene expression, and particularly histone acetylation pathway, to maternal obesity. Preconceptional weight loss appears beneficial for fetal growth, but some effects of previous obesity were retained in offspring transcriptome. During my PhD, I will precise:- the offspring phenotype using metabolomics of adult liver, olfactory bulb and hypothalamus (LC-HRMS),- the epigenomic analysis by an histone acetylation study in fetal liver (ChIP-seq,- the microbiota component with an analysis of maternal and offspring gut microbiota (16S rRNA-seq).The correlation of metabolic parameters, epigenomic state and gut microbiota will give us information about the mechanisms of maternal diet’s effects and their participation to adult health conditioning

Le statut métabolique maternal préconceptionnel influence le métabolisme hépatique des descendants mâles

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Pre-conceptional maternal metabolic status influences hepatic metabolome in male offspring

Sofiane Safi-Stibler a obtenu une bourse de voyage de la Société Française de Nutrition pour présenter ses travaux lors de ce congrès. Sofiane Safi-Stibler a obtenu un prix de présentation orale lors du congrès de la SF-DOHaD à Grenoble en 2018 afin de présenter ses travaux au cours du Congrès International de la DOHaD 2019 à Melbourne.International audienceBackground/AimsMaternal obesity is associated with fertility disorders, obstetric complications, and development of metabolic syndrome in offspring. The recommendation to overweight or obese women is to lose weight before pregnancy, but the impact of these prescriptions on the offspring health is insufficiently studied. Previous results on late-term mice fetuses have shown that maternal obesity leads to fetal growth restriction and to the modification of epigenetic machinery-related gene expression in fetal liver and placenta. Moreover, fetuses from the preconceptional weight loss maternal group normalize their growth, but some fetal genes stay differentially expressed.MethodWe analysed the metabolic phenotype of offspring born to control (CTRL), obese (OB) or weight loss after diet-induced obesity (WL) mothers. To highlight a possible conditioning effect, offspring were either fed a control (CD) or a high fat diet (HFD). Their metabolism and olfactory behavior were monitored for up to 6 months. Then, we analyzed the metabolome of three tissues involved in food intake and nutrient management (liver, olfactory bulb and hypothalamus) in male adult offspring.ResultsMultiple Factorial Analysis integration of offspring phenotypic data showed a major influence of the post-weaning diet and pointed a difference in HFD-fed males according to their maternal group (OB vs WL). This confirmed a sex-dependant metabolic conditioning by the maternal environment. The olfactory sensitivity, measured by electro-olfactogram, was reduced in WL male offspring, whatever the postnatal diet.The metabolomics study annotated 278, 258 and 200 metabolites in the liver, olfactory bulb and hypothalamus respectively. Again, the post-weaning diet had a major effect in the three tissues but interestingly, the maternal group also influenced the hepatic metabolome of adult offspring.ConclusionsThese data, integrating metabolism, olfactory behavior and metabolome, provide new and original information on the effects of preconceptional maternal metabolic status in the offspring health conditioning upon diet challenges

Differential effects of post-weaning diet and maternal obesity on mouse liver and brain metabolomes

International audienceNutritional changes during developmental windows are of particular concern in offspring metabolic disease. Questions are emerging concerning the role of maternal weight changes before conception, particularly for weight loss, in the development of diet-related disorders. Understanding the physiological pathways affected by the maternal trajectories in the offspring is therefore essential, but a broad overview is still lacking. We recently reported both metabolic and behavioral negative outcomes in offspring born to obese or weight-loss mothers and fed a control of high-fat diet, suggesting long-term modeling of metabolic pathways needing to be further characterized. Using non-targeted LC–HRMS, we investigated the impact of maternal and post-weaning metabolic status on the adult male offspring’s metabolome in three tissues involved in energy homeostasis: liver, hypothalamus and olfactory bulb. We showed that post-weaning diet interfered with the abundance of several metabolites, including 1,5-anhydroglucitol, saccharopine and β-hydroxybutyrate, differential in the three tissues. Moreover, maternal diet had a unique impact on the abundance of two metabolites in the liver. Particularly, anserine abundance, lowered by maternal obesity, was normalized by a preconceptional weight loss, whatever the post-weaning diet. This study is the first to identify a programming long-term effect of maternal preconception obesity on the offspring metabolome

Effect of maternal obesity and preconceptional weight loss on foeto-placental growth and offspring health in mice: expression of epigenetic modifiers at the interface with metabolism

Anne Gabory a reçu le prix du meilleur poster. Cette distinction a été offerte par l'Institute for Neuroscience, D-HEST, ETH Zurich.Effect of maternal obesity and preconceptional weight loss on foeto-placental growth and offspring health in mice: expression of epigenetic modifiers at the interface with metabolism. Epigenetic Inheritance Symposium 201