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Le concept de DOHaD (Developmental Origins of Health and Disease) qui découle de la théorie de Barker, replace l’origine des maladies métaboliques de l’adulte au moment du développement fœtal et/ou périnatal. De nombreuses données épidémiologiques indiquent qu’une dysnutrition maternelle (dénutrition, surnutrition) a des répercussions sur la croissance fœtale qui se traduisent par une anomalie du poids à la naissance (retard de croissance intra utérin : RCIU / gros poids de naissance : Macrosomie) et prédisposent l’individu au développement des maladies métaboliques. Afin de mieux comprendre les mécanismes susceptibles de transmettre de génération en génération cette vulnérabilité métabolique, nous avons développé un modèle transgénérationnel chez le rat associant la programmation fœtale chez la F0 par dénutrition maternelle (modèle FR30) et une dysnutrition chez la F1 avec un régime alimentaire hyperlipidique.Nos résultats montrent qu’une restriction alimentaire de 70% durant toute la grossesse (modèle FR30) contribue à une sensibilité accrue chez la descendance F1 femelle au développement de traits de syndrome métabolique. Les femelles F1 issues de mères dénutries présentent à l’âge adulte une intolérance au glucose et une hyperleptinémie. Les femelles de la F1 soumises à un régime hyperlipidique « high fat » (HF) ne présentent pas d’obésité que ce soit celles issues de mères contrôle que de mères dénutries. La faible appétence du régime, et la carence en hydrates de carbone qui l’accompagnent ne permettent pas le développement de l’obésité. En revanche, ce régime accentue les perturbations métaboliques chez des animaux sensibilisés par la programmation.Lorsque les femelles F1 sont mises en reproduction, on observe qu’en réponse à la programmation fœtale (FR) et/ou au régime alimentaire (Standard ou HF) la trajectoire de croissance dans la descendance F2 conduit à des phénotypes différents à la naissance. Les nouveau-nés de mères F1 issues de mères C ou FR et ayant suivi un régime HF en prégestation et en gestation (C HF-HF et FR HF-HF) ont un RCIU. A l’inverse, les nouveau-nés issus de mères F1 issues de mères dénutries et ayant eu un régime HF en prégestation puis un régime standard durant la gestation (FR HF-S) ont une macrosomie. Les perturbations métaboliques et hormonales des mères F1 ne pouvant expliquer à elles seules la survenue de ces phénotypes, nous nous sommes intéressés à l’organe situé à l’interface entre les compartiments maternels et fœtaux permettant le dialogue entre la mère et le fœtus : le placenta.L’analyse morphologique et moléculaire du placenta nous indique que cet organe est non seulement sensible aux modifications métaboliques de la mère, mais s’adapte à la demande du fœtus. On observe de fortes variations géniques qui se traduisent par une surexpression ou sous expressions géniques selon le phénotype observé RCIU ou macrosomie. Il est important de noter que les variations présentent un dimorphisme sexuel. Nos travaux suggèrent donc que les phénotypes de RCIU ou macrosomie sont le résultat d’anomalies métaboliques et hormonales maternelles mais également de l’adaptation génique placentaire sexe-spécifique. / The concept of DOHaD (Developmental Origins of Health and Disease) which derives from the theory of Barker, replace the origin of metabolic diseases in adults during fetal development and / or perinatal period. Many epidemiological data indicate that maternal dysnutrition (undernutrition, overnutrition) affects fetal growth showing abnormal birth weight (intrauterine growth retardation : IUGR / large birth weight macrosomia) and predispose individuals to development of metabolic diseases. To better understand the mechanisms invovle in transmission of the metabolic vulnerability from one generation to another, we have developed a model combining transgenerational rat fetal programming in the F0 by maternal undernutrition (model FR30) and dysnutrition in F1 with an hyperlipidic diet.Our results show that dietary restriction of 70% throughout pregnancy (FR30 model) contributes to emphasize development of metabolic syndrome traits into female F1 progeny. F1 females from undernourished mothers have an adult glucose intolerance and hyperleptinemia. These metabolic disturbances will be increase by a high fat diet (HF) but will not lead to obesity in female F1 regardless of the mother (F0) diet/statut. This can be explain by the low palatability of the diet, and the lack of carbohydrates largely involve in the development of obesity. These F1 phenoypes conduce to different F2 phenotypes at birth depending of fetal growth trajectory.Newborns from F1 mothers C or FR with HF diet during pregestation and gestation (C HF-HF and FR HF-HF) present IUGR. In contrast, infants born from F1 undernourished mothers with HF diet during pregestation following by standard diet during pregnancy (FR HF-S) show macrosomia. Like metabolic and hormonal disturbances into F1 mothers can not explain themselves the occurrence of these phenotypes, we studied the organ at the interface between maternal and fetal compartments in charge of the crosstalk between mother and fetus : the placenta. Morphological and molecular analysis indicate that placenta is not only sensitive to metabolic changes in the mother, but also able to adapt to the fetus needs. We observe strong correlation between gene expression (decrease or increase) and phenotype (IUGR/macrosomia) with gender specificity.Our work therefore suggests that IUGR or macrosomia phenotypes are not only depending on maternal hormonal and metabolic abnormalities but also in the sex-specific placental gene response to these exposure.

Based on a large series of epidemiological studies, it has been proposed that exposure to an increased nutrient supply before birth increases the risk of developing obesity in postnatal life. The physiological mechanisms underlying the association between increased nutrition before birth and later obesity are, however, poorly understood. This thesis has investigated the impact of an increased fetal nutrient supply on the programming of key systems within the appetite - regulating network and / or the adipocytes before and after birth. The studies in this thesis have demonstrated that plasma concentrations of the adipostatic hormone leptin are directly related to adiposity and the size of adipose cells in fetuses of ewes fed at or above maintenance energy requirements, which suggests that leptin may act as a peripheral signal of fat mass before birth. It has also been demonstrated that the components of the central network for appetite regulation are expressed in the hypothalamus of the fetal sheep from at least 110 d gestation ( term = 150 ± 3 d gestation ), and that the expression of the appetite - regulating neuropeptides is responsive to signals of increased nutrient supply before birth. This thesis has also demonstrated that an increase in maternal nutrition in late pregnancy results in increases in both food intake and glucose concentrations in the lamb in early postnatal life and in a significant increase in subcutaneous adiposity on postnatal day 30. Importantly, increased maternal nutrition resulted in an altered relationship between signals of increased fat mass and nutrition and expression of a central appetiteinhibitory neuropeptide, CART, in the lamb hypothalamus. It was also demonstrated that there was an interaction between the prenatal and postnatal nutritional environments in the determination of lipogenesis in the early postnatal period. The findings presented in this thesis provide evidence that programmed changes to the sensitivity of the appetite - regulating neuropeptides to signals of increased adiposity and nutritional status in early postnatal life are an important part of the physiological pathway through which exposure to an increased nutrient supply before birth may lead to an increased risk of obesity in later life. / Thesis (Ph.D.)--School of Molecular and Biomedical Science, 2006.

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Thesis (Ph.D.)--University of Adelaide, School of Molecular and Biomedical Sciences, Discipline of Physiology, 2004. / Includes list of papers arising from this thesis. "July 2004" Includes bibliographical references (leaves 253-297). Also available online.

Thesis (Ph.D.)--University of Adelaide, School of Molecular and Biomedical Sciences, Discipline of Physiology, 2004. / Includes list of papers arising from this thesis. "July 2004" Includes bibliographical references (leaves 253-297). Also available in print form.

Cartas al editor