IGF-1 Induces GHRH Neuronal Axon Elongation during Early Postnatal Life in Mice

PLoS One. 2017 Jan 11;12(1):e0170083. doi: 10.1371/journal.pone.0170083. eCollection 2017.

Abstract

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 postnatal period with programming of the growth trajectory.

MeSH terms

  • Animals
  • Animals, Newborn
  • Axons / drug effects*
  • Axons / metabolism
  • Axons / physiology
  • Female
  • Growth Hormone-Releasing Hormone / metabolism*
  • Growth and Development / drug effects
  • Insulin-Like Growth Factor I / pharmacology*
  • Insulin-Like Growth Factor I / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neuronal Outgrowth / drug effects*
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neurons / physiology

Substances

  • Insulin-Like Growth Factor I
  • Growth Hormone-Releasing Hormone

Grant support

This study was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), l’Université Pierre et Marie Curie (Sorbonne Universités, UPMC Univ Paris 06), the institute of Cardiometabolism and Nutrition (IHU ICAN), Sandoz-France laboratories, and the Premup foundation. P.M. was supported by an ANR grant (ANR-2010-BLAN-1415-01). E.M. was supported by CDD-Inserm. L.D. was supported by a PhD grant from the French Ministry for Education and Research Training and from the Société Française d’Endocrinologie et Diabètologie Pédiatrique (SFEDP, grant Sandoz Biopharmaceuticals France).