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• W2918185217 abstract "Growth hormone (GH) is an anabolic hormone that regulates linear growth during critical developmental stages, and maintains healthy metabolism throughout life. The ultradian rhythm of GH secretion is orchestrated by intricate actions of hypothalamic stimulatory growth hormone-releasing hormone (GHRH) and inhibitory somatostatin (SST), acting on somatotrophs in the anterior pituitary gland (APG). The interplay between GHRH and SST generates the pulsatile pattern of GH release. This patterned release is defined by the amount of GH secreted per burst (amplitude of GH release) and the secretory pulse frequency and regularity (as denoted by pulse number and approximate entropy (ApEn); defined using deconvolution analysis). The patterned release of GH is entrained to meet physiological demands, with numerous central and peripheral factors regulating GHRH and SST actions. For example, key modulators of food intake and peripheral factors that signal adiposity are thought to override GHRH- and SST-mediated GH release, entraining the amount and pattern of GH release relative to calorie provision and peripheral factors associated with food intake and adiposity. Therefore, it is firstly hypothesised that the suppression of GH secretion in obesity does not occur in response to endocrine dysfunction, rather it occurs alongside progressive weight gain, and thus changes in GH feedback to promote the progressive suppression of GH relative to increased fat mass.Data within this thesis confirms the suppression of peak and total GH release in obese mice, further demonstrating a progressive suppression of GH release relative to increased body weight and adiposity in both obese and non-obese mice. Thus, it is proposed that GH deficiency in obesity may represent physiological changes in the regulation of GH release, rather than pathological changes that culminate with the development of obesity. To clarify the association between metabolic or peripheral factors that signal adiposity with spontaneous release of GH, correlation analyses revealed an inverse relationship between epididymal fat mass, leptin (secreted proportionally to adiposity) and insulin, and parameters associated with the amount of GH released in wild-type (WT) male mice. No association was observed specific in GH pulse patterning, confirming that GH patterning (represented by the interactions of hypothalamic pulse generators – GHRH and SST) remains intact regardless of feedback pressure to reduce the amount of GH release.Given compelling evidence from pharmacological studies and modified-ghrelin animal models demonstrated that acyl-ghrelin (biologically active form of ghrelin) has the capacity to induce adiposity and amplify peak GH release, and the level of acyl-ghrelin in circulation is age-dependent, it is hypothesised that acyl-ghrelin modulates the pulsatile release of growth hormone relative to adiposity and age. To address the endogenous role of acyl-ghrelin relative to the pulsatile pattern of GH secretion, spontaneous GH release in ad libitum (ad lib) fed, conscious and free-moving male mice with germline deletion of ghrelin-o-acyltransferase (goat) was assessed. These animals (goat-/-) do not have acyl-ghrelin, and thus offer a unique opportunity to define the importance of acyl-ghrelin in regulating the amount and pulsatile pattern of GH secretion. Measures were extended to include transcript expression for key hypothalamic regulators of GH release, and peripheral factors modulated relative to GH release. As anticipated, data shows a significant reduction in the amplitude of GH release in goat-/- mice compared to age-matched WT mice. Data demonstrate comparable levels of adiposity in WT and goat-/- mice. Moreover, the negative association between adiposity and GH release is conserved in both genotypes. As such, further studies were conducted to interrogate the in vivo role of acyl-ghrelin in regulating GH release relative to age.The amplitude of GH release was remarkably low in younger goat-/- mice compared to age-matched WT mice. Although it is thought that the reduction in GH release is coupled to an age-associated decline in acylated ghrelin levels, this was not observed in goat-/- mice when compared with age-matched WT mice, potentially due to low levels of GH release at a young age. Moreover, as epididymal fat weight from age-matched WT and goat-/- mice was comparable, the reduction in the amount of GH secreted in young goat-/- mice likely occurred independent of feedback that is specific to adiposity. An increase in GH pulse frequency was observed alongside irregular pulse patterning in goat-/- mice. This was characterised by an increase in the number of GH pulses and ApEn observed during extended secretory events. This overall change in GH patterning in goat-/- mice did not coincide with changes in hypothalamic Ghrh, Sst, Neuropeptide Y (Npy) or Gh secretagogue receptor (Ghsr) gene expression, or pituitary GH content, suggesting that loss of acyl-ghrelin does not alter the presence of components of central systems thought to contribute to the synthesis and release of GH. Rather, it is proposed that loss of acyl-ghrelin may alter interactions between these hypothalamic components of GH release. Of interest, despite reduced GH release, body length remained similar between goat-/- and WT mice. Furthermore, peripheral levels of insulin-like growth factor 1 (IGF-1) in goat-/- mice were positively correlated with an increase in GH pulse frequency. Thus, sustained or increased IGF-1 release in goat-/- mice may compensate for the effects of reduced peak GH release (in young adult mice) on linear growth.In summary, observations within this thesis demonstrate that, 1) weight gain and increased adiposity contributes to a progressive reduction in the amount of GH release; 2) altered secretion of leptin (as an adipostat) and insulin (a metabolic modulator of glucose metabolism) may not directly impact GH pulse patterning, rather these factors are proposed to contribute to progressive reduction in GH release relative to fat mass, and thus may contribute to the feedback regulation of peak and total GH release as obesity develops;  3) germline loss of acyl-ghrelin contributes to derangements in the amount and patterning of GH release independent of adiposity and 4) the loss of acyl-ghrelin results in a rise in the frequency and irregularity of GH pulses, which in turn may recover peripheral levels of IGF-1 to sustain linear growth. While these factors largely entrain the amount and patterning of GH release, contributing to progressive changes to meet physiological needs, derangements in GH release may be detrimental to the long-term anabolic actions of GH." @default.
• W2918185217 created "2019-03-11" @default.
• W2918185217 creator A5008085698 @default.
• W2918185217 date "2018-07-12" @default.
• W2918185217 modified "2023-09-27" @default.
• W2918185217 title "The effect of adiposity, age and deletion of acyl-ghrelin on pulsatile growth hormone release in male mice" @default.
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