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

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.

Regulation of growth: Epigenetic mechanisms?

“…Since GHRH neurons innervate the median eminence through a posteroventral loop highly difficult to follow by classical immunohistochemistry, we applied an in vitro approach by cultivating explants of arcuate nucleus. In agreement with our hypothesis, we observed that IGF-I significantly stimulates the axon growth of GHRH neurons in 24 hours in arcuate explants harvested from normally fed pups [17]. Interestingly, this effect seems preferential since no stimulations were observed for other populations of the arcuate nucleus studied all-at once (i.e.…”

“…The axon growth stimulating effect of IGF-I on GHRH neurons involves both the PI3K/AKT and, in a lower extent, the MERK/ERK signaling pathways as revealed by co-stimulations of IGF-I with LY294002 and PD0325901 specific inhibitors, respectively. However, when explants of arcuate nucleus were harvested from restricted pups, we observed that GHRH neurons lost their capacities to answer to IGF-I stimulation despite a controlled in vitro environment [17]. Western blot experiments on arcuate nucleus explants suggest that the absence of axon elongation observed for GHRH neurons in restricted pups is associated with impaired activation of the PI3K/AKT signaling pathway, whereas the activation capacity of the ERK/MEK pathway is maintained.…”

Manipulation of the Growth Hormone-Insulin-Like Growth Factor (GH-IGF) Axis: A Treatment Strategy to Reverse the Effects of Early Life Developmental Programming

“…It has been well-established that adverse developmental programming disrupts the normal wiring of the pathways that regulate energy balance via a disruption in neurite outgrowth in the ARC and changes in the expression of anorixigenic/orexigenic factors, including neuropeptide Y (NPY), proopiomelanocortin (POMC), and agouti-related peptide (AgRP). Similarly, it is well-known that the developmental settings of the somatotropic neuroendocrine axis are highly sensitive to alterations in early postnatal nutrition, suggesting that this subset of hypothalamic neurons (NPY, POMC, and AgRP) are particularly sensitive to changes in nutrition during the perinatal period [ 55 ]. However, the interactions between the factors regulating energy balance and GH-releasing hormone (GHRH) neurons in the ARC in the setting of early life programming remain poorly defined, and may reflect the “adaptive plasticity” of somatotropic functions allowing individuals to modify (i.e., decelerate) growth and conserve energy resources as per the PARS hypothesis, and thereby improving fitness in challenging postnatal environments [ 56 ].…”

“…However, the interactions between the factors regulating energy balance and GH-releasing hormone (GHRH) neurons in the ARC in the setting of early life programming remain poorly defined, and may reflect the “adaptive plasticity” of somatotropic functions allowing individuals to modify (i.e., decelerate) growth and conserve energy resources as per the PARS hypothesis, and thereby improving fitness in challenging postnatal environments [ 56 ]. In cases of UN during lactation in the mouse, offspring show decreased circulating IGF-1 concentrations, which are associated with a reduced innervation of the median eminence by GHRH axons compared to control pups in the early neonatal period [ 55 ]. In vitro, IGF-1 stimulation preferentially stimulates axon elongation of GHRH neurons from normally nourished pups, whereas GHRH neurons derived from pups of UN mothers failed to respond to IGF-1 stimulation [ 55 ].…”

“…In cases of UN during lactation in the mouse, offspring show decreased circulating IGF-1 concentrations, which are associated with a reduced innervation of the median eminence by GHRH axons compared to control pups in the early neonatal period [ 55 ]. In vitro, IGF-1 stimulation preferentially stimulates axon elongation of GHRH neurons from normally nourished pups, whereas GHRH neurons derived from pups of UN mothers failed to respond to IGF-1 stimulation [ 55 ]. These effects appeared to be cell type-specific, as other ARC neurons, including AgRP, did not respond to IGF stimulation.These data highlight a cell-selective role for IGF-1 in axon elongation, and as part of the complex cellular mechanism that links UN during the early postnatal period with later programming of body growth trajectory.…”