Des-acyl ghrelin induces food intake by a mechanism independent of the growth hormone secretagogue receptor

Endocrinology. 2006 May;147(5):2306-14. doi: 10.1210/en.2005-1357. Epub 2006 Feb 16.

Abstract

Ghrelin, an acylated peptide produced predominantly in the stomach, stimulates feeding and GH secretion via interactions with the GH secretagogue type 1a receptor (GHS-R1a), the functionally active form of the GHS-R. Ghrelin molecules exist in the stomach and hypothalamus as two major endogenous forms, a form acylated at serine 3 (ghrelin) and a des-acylated form (des-acyl ghrelin). Acylation is indispensable for the binding of ghrelin to the GHS-R1a. Ghrelin enhances feeding via the neuronal pathways of neuropeptide Y and orexin, which act as orexigenic peptides in the hypothalamus. We here studied the effect of des-acyl ghrelin on feeding behavior. Intracerebroventricular (icv) administration of rat des-acyl ghrelin to rats or mice fed ad libitum stimulated feeding during the light phase; neither ip nor icv administration of des-acyl ghrelin to fasting mice suppressed feeding. The icv administration of des-acyl ghrelin induced the expression of Fos, a marker of neuronal activation, in orexin-expressing neurons of the lateral hypothalamic area, but not neuropeptide Y-expressing neurons of the arcuate nucleus. Peripheral administration of des-acyl ghrelin to rats or mice did not affect feeding. Although icv administration of ghrelin did not induce food intake in GHS-R-deficient mice, it did in orexin-deficient mice. In contrast, icv administration of des-acyl ghrelin stimulated feeding in GHS-R-deficient mice, but not orexin-deficient mice. Des-acyl ghrelin increased the intracellular calcium concentrations in isolated orexin neurons. Central des-acyl ghrelin may activate orexin-expressing neurons, perhaps functioning in feeding regulation through interactions with a target protein distinct from the GHS-R.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Chromatography, High Pressure Liquid
  • Cytosol / metabolism
  • Feeding Behavior*
  • Gastric Mucosa / metabolism
  • Ghrelin
  • Growth Hormone / metabolism
  • Hypothalamus / metabolism
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Movement
  • Neurons / metabolism
  • Neuropeptide Y / metabolism
  • Neuropeptides / metabolism
  • Orexin Receptors
  • Orexins
  • Peptide Hormones / metabolism
  • Peptide Hormones / pharmacology*
  • Peptides / chemistry
  • Proto-Oncogene Proteins c-fos / metabolism
  • Rats
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, Ghrelin
  • Receptors, Neuropeptide
  • Time Factors

Substances

  • Ghrelin
  • Intracellular Signaling Peptides and Proteins
  • Neuropeptide Y
  • Neuropeptides
  • Orexin Receptors
  • Orexins
  • Peptide Hormones
  • Peptides
  • Proto-Oncogene Proteins c-fos
  • Receptors, G-Protein-Coupled
  • Receptors, Ghrelin
  • Receptors, Neuropeptide
  • ghrelin, des-n-octanoyl
  • Growth Hormone
  • Calcium