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

Dornonville de la Cour, Charlotta LU (2004)
Abstract (Swedish)
Popular Abstract in Swedish

Magsäcken är ett av kroppens största peptidhormon-producerande organ. Peptid-hormon härifrån är inte bara viktiga för att reglera olika fysiologiska funktioner i magsäcken t.ex. saltsyrasekretion och motilitet, utan också för andra funktioner i kroppen. Fortfarande vet vi mycket lite om de hormon som produceras i magsäcken. Några av de hormon man identifierat har okända fysiologiska funktioner och andra återstår att identifiera. Sedan länge har man varit på jakt efter magsäckshormon som misstänks kunna påverka bentillväxt och insulinfrisättning från bukspottskörteln, eftersom gastrektomi (kirurgiskt borttagande av magsäcken) leder till osteopeni (benskörhet) och försämrad insulinfrisättning efter... (More)
Popular Abstract in Swedish

Magsäcken är ett av kroppens största peptidhormon-producerande organ. Peptid-hormon härifrån är inte bara viktiga för att reglera olika fysiologiska funktioner i magsäcken t.ex. saltsyrasekretion och motilitet, utan också för andra funktioner i kroppen. Fortfarande vet vi mycket lite om de hormon som produceras i magsäcken. Några av de hormon man identifierat har okända fysiologiska funktioner och andra återstår att identifiera. Sedan länge har man varit på jakt efter magsäckshormon som misstänks kunna påverka bentillväxt och insulinfrisättning från bukspottskörteln, eftersom gastrektomi (kirurgiskt borttagande av magsäcken) leder till osteopeni (benskörhet) och försämrad insulinfrisättning efter måltid. 1999 identifierades ett tidigare okänt peptidhormon i magsäcken som fick namnet ghrelin. Vi kunde visa att ghrelin produceras av de så kallade A-lika cellerna i magslemhinnan och att det frisätts under fasta. Vad som reglerar ghrelinsekretionen är inte utrett men vi visade att somatostatin och GRP/bombesin hämmar frisättningen medan sekretin, adrenalin, noradrenalin och endothelin stimulerar. Vi studerade också ghrelins roll i olika fysiologiska processer. Ghrelin tycks inte delta i regleringen av magens saltsyrasekretion eller påverka de endokrina celler som är involverade i denna process (G celler, ECL celler och D celler). Däremot kan ghrelin vara involverat i magens motilitet, då det påskyndar magsäckstömning. Vidare fann vi att mycket höga ghrelin-doser (ofysiologiska/farmakologiska) frisatte insulin medan lägre, mer fysiologiska mängder hämmade eller var utan effekt. Vi studerade ghrelins effekter på födointag, kroppsvikt, fett och ben genom att jämföra möss som fått dagliga injektioner av ghrelin, med gastrektomerade. Gastrektomi leder till att 80% av allt cirkulerande ghrelin försvinner. Efter åtta veckor vägde de gastrektomerade mössen mindre än intakta möss och de uppvisade osteopeni och mindre mängd fett. Det dagliga födointaget påverkades inte av gastrektomi. Ghrelinbehandling normaliserade vikten och mängden fett men påverkade inte benmassan på gastrektomerade möss. Ghrelinbehandling av intakta djur påverkade ej födointaget, kroppsvikten eller benmassan men ökade mängden fett. (Less)
Abstract
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... (More)
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. (Less)
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author
opponent
  • Professor Jansson, John-Olov
organization
publishing date
type
Thesis
publication status
published
subject
keywords
toxicology, Farmakologi, pharmacognosy, pharmacy, Pharmacological sciences, bone metabolism, energy homeostasis, glucagon, insulin, secretion, pancreastatin, somatostatin, histamine, gastrin, gastric acid secretion, ghrelin, gastric motility, A-like cells, farmakognosi, farmaci, toxikologi
pages
149 pages
publisher
Department of Experimental Medical Science, Lund Univeristy
defense location
Fernström lecture hall, BMC
defense date
2004-05-14 10:15
ISBN
91-628-6058-5
language
English
LU publication?
yes
id
5f5960ce-9366-4a05-a515-5ac400efc59c (old id 466876)
date added to LUP
2007-09-07 13:15:29
date last changed
2016-09-19 08:45:13
@phdthesis{5f5960ce-9366-4a05-a515-5ac400efc59c,
  abstract     = {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.},
  author       = {Dornonville de la Cour, Charlotta},
  isbn         = {91-628-6058-5},
  keyword      = {toxicology,Farmakologi,pharmacognosy,pharmacy,Pharmacological sciences,bone metabolism,energy homeostasis,glucagon,insulin,secretion,pancreastatin,somatostatin,histamine,gastrin,gastric acid secretion,ghrelin,gastric motility,A-like cells,farmakognosi,farmaci,toxikologi},
  language     = {eng},
  pages        = {149},
  publisher    = {Department of Experimental Medical Science, Lund Univeristy},
  school       = {Lund University},
  title        = {Origin, release and functional significance of the novel gastric hormone ghrelin},
  year         = {2004},
}