Abstract
Using preproghrelin-deficient mice (Ghrl-/-), we previously observed that preproghrelin modulates pulsatile growth hormone (GH) secretion in post-pubertal male mice. However, the role of ghrelin and its derived peptides in the regulation of growth parameters or feeding in females is unknown. We measured pulsatile GH secretion, growth, metabolic parameters and feeding behavior in adult Ghrl-/- and Ghrl+/+ male and female mice. We also assessed GH release from pituitary explants and hypothalamic growth hormone-releasing hormone (GHRH) expression and immunoreactivity. Body weight and body fat mass, linear growth, spontaneous food intake and food intake following a 48-h fast, GH pituitary contents and GH release from pituitary explants ex vivo, fasting glucose and glucose tolerance were not different among adult Ghrl-/- and Ghrl+/+ male or female mice. In vivo, pulsatile GH secretion was decreased, while approximate entropy, that quantified orderliness of secretion, was increased in adult Ghrl-/- females only, defining more irregular GH pattern. The number of neurons immunoreactive for GHRH visualized in the hypothalamic arcuate nucleus was increased in adult Ghrl-/- females, as compared to Ghrl+/+ females, whereas the expression of GHRH was not different amongst groups. Thus, these results point to sex-specific effects of preproghrelin gene deletion on pulsatile GH secretion, but not feeding, growth or metabolic parameters, in adult mice.
Highlights
The ghrelin gene (GHRL) encodes proghrelin prohormone, which in turn gives rise to acylated and nonacylated ghrelin as well as obestatin, which are mainly secreted from cells of the stomach [1]
Adult Ghrl-/- females display, decreased amplitude of growth hormone (GH) secretion and increased irregularity of secretion accompanied by increased immunoreactive signal for growth hormonereleasing hormone (GHRH) in the arcuate nucleus (ArcN) without change in the pituitary GH content or GH secretion from pituitary explants
Endogenous ghrelin seems to regulate the amplitude of GH secretion in healthy men since ghrelin levels and GH pulse amplitude strongly correlate [49]
Summary
The ghrelin gene (GHRL) encodes proghrelin prohormone, which in turn gives rise to acylated and nonacylated ghrelin as well as obestatin, which are mainly secreted from cells of the stomach [1]. Ghrelin administration in humans and rodents induces a Preproghrelin, GH Pulsatility in Mice plethora of effects [2, 3] including stimulation of GH secretion [2, 4]. In rodents, this effect is principally mediated through GHRH neurons of the hypothalamic arcuate nucleus (ArcN) [5]. Mice lacking the enzyme ghrelin-O-acyltransferase (GOAT), which n-acetylates ghrelin, and mice with ablation of proghrelin-expressing cells show no food intake, body growth nor body weight alterations [18,19,20,21,22]. GHSR-deficient (Ghsr-/-) mice usually show more robust alterations, as compared to Ghrl-/- mice, which has been attributed to the fact that the latter retain ligand-independent effects of GHSR and/or signaling of other proghrelin-derived peptides [25, 29]
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