Origin, release and functional significance of the novel gastric hormone ghrelin

Detta är en avhandling från Department of Experimental Medical Science

Sammanfattning: The novel gastric hormone ghrelin was discovered by virtue of its ability to release growth hormone (GH) via interaction with the so-called GH-secretagogue receptor (GHS-R). Earlier only synthetic agents were known to bind with the GHS-R, hence, ghrelin is the first identified endogenous ligand. GHS-R occurs in the pituitary and hypothalamus but also in several peripheral tissues, suggesting the involvement of ghrelin in physiological processes other than controlling GH secretion. The aims of this study was to identify the cellular source of ghrelin, the mechanisms that control the secretion of ghrelin, and the significance of ghrelin in various physiological processes. Ghrelin was found to be manufactured by endocrine cells, referred to as A-like cells, mainly present in the oxyntic mucosa of the stomach. Gastric A-like cells were few at birth and reached adult numbers at 4-5 weeks of age. The development of A-like cells was shown to be independent of gastrin. Circulating concentrations of ghrelin were low at birth, reaching adult levels during the period of weaning (2-3 weeks postnatally). Ghrelin was found to be mobilized in response to food deprivation. Although the mechanisms controlling the secretion of ghrelin remain to be clarified, our results suggest that secretin, endothelin and catecholamines are possible stimulators of ghrelin release, while GRP/bombesin and somatostatin inhibit. Ghrelin was a powerful stimulator of gastric emptying but did not affect gastric acid secretion or secretion from ECL cells (histamine, pancreastatin), gastrin (G) cells or somatostatin (D) cells.Ghrelin had biphasic effects on insulin release, stimulating at high concentrations while inhibiting (or failing to affect) at low. Glucagon secretion was stimulated by ghrelin in vitro but not in vivo. It is doubtful whether the effects of ghrelin on insulin/glucagon secretion are physiologically significant. Finally, the effects of ghrelin on food intake, body weight and specific body compartments were investigated following 8 weeks of hypoghrelinemia (gastrectomy, Gx) or hyperghrelinemia (daily injection of ghrelin). Gastrectomy reduced the body weight gain and the amount of bone, fat and lean body mass. There was no difference in daily food intake between hypo- and hyperghrelinemic mice. Ghrelin administration prevented the effects of Gx on fat, lean tissue and body weight but had no effect on bone. Ghrelin raised the amount of fat but did not increase the body weight in sham-operated mice.

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