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Early Postnatal Nutrition Determines Somatotropic Function in Mice

Institut National de la Santé et de la Recherche Médicale, Centre De Recherche Saint Antoine (L.K., C.D.M.F., P.L., J.X., N.B., Y.L.B., M.H.), F-75012 Paris, France; Université Pierre et Marie Curie (L.K., C.D.M.F., J.X., C.C., Y.L.B., M.H.), F-75005 Paris, France; Institut National de la Santé et de la Recherche Médicale U702 (C.C.), Hôpital Tenon, F-75020 Paris, France; and Assistance Publique-Hôpitaux de Paris (Y.L.B.), Hôpital Trousseau, F-75012 Paris, France

Address all correspondence and requests for reprints to: Laurent Kappeler or Martin Holzenberger, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 893, Hôpital Saint-Antoine, Bât. Kourilsky, 184 rue du Faubourg Saint-Antoine, F-75012 Paris, France. E-mail: laurent.kappeler{at}inserm.fr, or martin.holzenberger{at}inserm.fr, respectively.

Increasing evidence suggests a developmental origin for a number of human diseases, notably after intrauterine or postnatal nutrient deprivation. Nutritional changes readily translate into alterations of somatic growth. However, whereas intrauterine growth retardation often shows postnatal catch-up growth, recovery from food restriction immediately after birth is limited. Therefore, we investigated whether early postnatal nutrition (undernutrition and overfeeding) modifies plasticity of growth through developmental control of the somatotropic hormone axis. We used cross-fostering in mice to induce changes in early nutrition, and examined endocrine growth regulation and the development of specific disease phenotypes in adults. We showed that underfeeding during the early postnatal period delayed growth, whereas overfeeding accelerated it. In both cases, final body size was permanently altered. We found coordinated alterations in pituitary GH, plasma IGF-I and acid labile subunit, and gene expression of hypothalamic GHRH during postnatal development. These changes were consistent with the observed phenotypes. Alterations in the somatotropic axis persisted throughout adulthood. Although limited to the early postnatal period, both underfeeding and overfeeding led to reduced glucose tolerance later in life. These metabolic abnormalities were in line with defective insulin secretion in restricted mice and insulin resistance in overfed mice. Moreover, both restricted and overfed mice had increased arterial blood pressure, suggestive of vascular impairment. Our findings indicate a significant link between early postnatal diet, somatotropic development, and specific late onset diseases in mice. We suggest that, together with other hormones like leptin, IGF-I may play a role in modulating hypothalamic stimulation of the developing somatotropic function.

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