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.
Highlights
Normal development of both cognitive and somatic functions requires suitable nutrition of the developing fetus and newborns during the perinatal period [1]
We examined the potential ability of IGF-1 to regulate axonal outgrowth of Growth Hormone Releasing Hormone (GHRH) neurons, and how it is controlled by nutrition using in vitro arcuate explant cultures
This was associated with lower pituitary growth hormone (GH) mRNA levels (Fig 1C) and permanent pituitary hypoplasia of GHsecreting somatotroph cells from 20 days of age (Fig 1D), as we previously showed in adults [6,7]
Summary
Normal development of both cognitive and somatic functions requires suitable nutrition of the developing fetus and newborns during the perinatal period [1]. Insufficient food supplies during the early postnatal period affect body growth as well as the risk of developing cardiovascular and metabolic diseases in adulthood. This is in agreement with the developmental origin of health and adult diseases (DOHaD), after intrauterine growth retardation, which accounts for 5% of births [2]. The developmental settings of the somatotropic axis are highly sensitive to early postnatal nutrition [6,7], suggesting that this subset of hypothalamic neurons is sensitive to nutritional supply during the perinatal period. The permanent growth delay phenotype resulting from caloric nutritional restriction during lactation [6] can be genetically mimicked by tissue-specific heterozygous inactivation of the IGF-1 receptor (IGF1R) in the central nervous system [7]
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