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Objective Individuals born with intrauterine growth retardation (IUGR) are more prone to cardio-metabolic diseases as adults, and environmental changes during the perinatal period have been identified as potentially crucial factors. We have studied in a preclinical model early-onset molecular alterations present before the development of a clinical phenotype. Methods We used a preclinical mouse model of induced IUGR, in which we modulated the nutrition of the pups during the suckling period, to modify their susceptibility to cardio-metabolic diseases in adulthood. Results Mice born with IUGR that were overfed (IUGR-O) during lactation rapidly developed obesity, hepatic steatosis and insulin resistance, by three months of age, whereas those subjected to nutrition restriction during lactation (IUGR-R) remained permanently thin and highly sensitive to insulin. Mice born with IUGR and fed normally during lactation (IUGR-N) presented an intermediate phenotype and developed insulin resistance by 12 months of age. Molecular alterations to the insulin signaling pathway with an early onset were observed in the livers of adult IUGR-N mice, nine months before the appearance of insulin resistance. The implication of epigenetic changes was revealed by ChIP sequencing, with both posttranslational H3K4me3 histone modifications and microRNAs involved. Conclusions These two changes lead to the coherent regulation of insulin signaling, with a decrease in Akt gene transcription associated with an increase in the translation of its inhibitor, Pten. Moreover, we found that the levels of the implicated miRNA19a-3p also decreased in the blood of young adult IUGR mice nine months before the appearance of insulin resistance, suggesting a possible role for this miRNA as an early circulating biomarker of metabolic fate of potential use for precision medicine., Highlights • Male mice are highly sensitive to changes in nutrition during the perinatal period. • Post-natal nutrition modulates metabolic diseases induced by IUGR in male mice. • Metabolic programming by perinatal nutrition involves epigenetic mechanisms. • Pre-symptomatic IUGR mice present molecular alterations of the insulin pathway. • Plasma miRNA19a-3p levels are associated with the development of insulin resistance.

International audience; Nutrition during the perinatal period programs body growth. Growth hormone (GH) secretion from the pituitary regulates body growth and is controlled by Growth Hormone Releasing Hormone (GHRH) neurons located in the arcuate nucleus of the hypothalamus. We observed that dietary restriction during the early postnatal period (i.e. lactation) in mice influences postnatal growth by permanently altering the development of the somatotropic axis in the pituitary gland. This alteration may be due to a lack of GHRH signaling during this critical developmental period. Indeed, underfed pups showed decreased insulin-like growth factor I (IGF-I) plasma levels, which are associated with lower innervation of the median eminence by GHRH axons at 10 days of age relative to normally fed pups. IGF-I preferentially stimulated axon elongation of GHRH neurons in in vitro arcuate explant cultures from 7 day-old normally fed pups. This IGF-I stimulating effect was selective since other arcuate neurons visualized concomitantly by neurofilament labeling, or AgRP immunochemistry, did not significantly respond to IGF-I stimulation. Moreover, GHRH neurons in explants from age-matched underfed pups lost the capacity to respond to IGF-I stimulation. Molecular analyses indicated that nutritional restriction was associated with impaired activation of AKT. These results highlight a role for IGF-I in axon elongation that appears to be cell selective and participates in the complex cellular mechanisms that link underfeeding during the early postna-tal period with programming of the growth trajectory.

International audience; Organism development is controlled by both genetic programs and the environment to insure a reproductive success as adults. Linear growth is an important part of the development and is mostly controlled by genetic factors. However, the variability of height in a given species does not seem to be specifically associated with SNP. This suggests that environment may play a crucial role. In agreement, an important part of height-related genes present CpG island in their proximal promoter, indicating potential involvement of epigenetic mechanisms. In mammals, the linear growth is regulated by the IGF system, with IGF-I and IGF-II during the fetal period, and IGF-I being included within the somatotropic axis during the postnatal period. Nutrition during the lactating period programs linear growth and adult size through a modulation of the somatotropic axis development and of the setting of its activity later on. The study of underlying mechanisms suggest two waves of programming, which involve both structural adaptation during the early postnatal period and permanent functional adaptation in adulthood. The former may involve a direct stimulation of axon growth of GHRH neurons by IGF-I in first weeks of life while the latter could involve permanent epigenetic modifications in adulthood.; Le développement de l’organisme est contrôlé à la fois par des programmes génétiques et par l’environnement afin d’assurer un succès reproductif à l’âge adulte. La croissance staturale est une partie importante du développement et est principalement contrôlée par des facteurs génétiques. Cependant, la variabilité de la taille chez une espèce donnée ne semble pas être entièrement sous la dépendance du background génétique. Ceci suggère que l’environnement pourrait jouer un rôle crucial. En accord avec cela, une proportion importante des gènes liés à la croissance présente un îlot CpG dans leur promoteur proximal, ce qui indique l’implication potentielle de mécanismes épigénétiques. Chez les mammifères, la croissance staturale est régulée par le système IGF, avec l’IGF-I et IGF-II durant la période fœtale et l’IGF-I étant inclus dans l’axe somatotrope lors la période postnatale. La nutrition pendant la période transitoire qu’est l’allaitement programme la croissance staturale et la taille adulte par une modulation du développement de l’axe somatotrope et de son activité à l’âge adulte. L’étude des mécanismes sous-jacents suggère deux vagues de programmation, qui impliquent à la fois une adaptation structurelle en période postnatale précoce et une adaptation fonctionnelle permanente chez l’adulte. La première semble impliquer une stimulation directe de la croissance axonale des neurones GHRH par l’IGF-I dans les premières semaines de vie, alors que la seconde pourrait impliquer des modifications épigénétiques permanentes à l’âge adulte.