Ghrelin, an endogenous growth hormone secretagogue, is a novel orexigenic peptide that antagonizes leptin action through the activation of hypothalamic neuropeptide Y/Y1 receptor pathway

Diabetes. 2001 Feb;50(2):227-32. doi: 10.2337/diabetes.50.2.227.


Ghrelin, an endogenous ligand for growth hormone secretagogue (GHS) receptor originally isolated from the stomach, occurs in the hypothalamic arcuate nucleus and may play a role in energy homeostasis. Synthetic GHSs have activated the hypothalamic arcuate neurons containing neuropeptide Y (NPY), suggesting the involvement of NPY in some of ghrelin actions. This study was designed to elucidate the role of ghrelin in the regulation of food intake. A single intracerebroventricular (ICV) injection of ghrelin (5-5,000 ng/rat) caused a significant and dose-related increase in cumulative food intake in rats. Ghrelin (500 ng/rat) was also effective in growth hormone-deficient spontaneous dwarf rats. Hypothalamic NPY mRNA expression was increased in rats that received a single ICV injection of ghrelin (500 ng/rat) (approximately 160% of that in vehicle-treated groups, P < 0.05). The ghrelin's orexigenic effect was abolished dose-dependently by ICV co-injection of NPY Y1 receptor antagonist (10-30 microg/rat). The leptin-induced inhibition of food intake was reversed by ICV co-injection of ghrelin in a dose-dependent manner (5-500 ng/rat). Leptin reduced hypothalamic NPY mRNA expression by 35% (P < 0.05), which was abolished by ICV co-injection of ghrelin (500 ng/rat). This study provides evidence that ghrelin is an orexigenic peptide that antagonizes leptin action through the activation of hypothalamic NPY/Y1 receptor pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Drug Combinations
  • Ghrelin
  • Growth Hormone / deficiency
  • Growth Hormone / metabolism*
  • Hypothalamus / drug effects
  • Hypothalamus / metabolism*
  • Injections, Intraventricular
  • Leptin / antagonists & inhibitors*
  • Leptin / pharmacology
  • Male
  • Neuropeptide Y / genetics
  • Neuropeptide Y / physiology*
  • Peptide Hormones*
  • Peptides / pharmacology
  • Peptides / physiology*
  • RNA, Messenger / antagonists & inhibitors
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley


  • Drug Combinations
  • Ghrelin
  • Leptin
  • Neuropeptide Y
  • Peptide Hormones
  • Peptides
  • RNA, Messenger
  • Growth Hormone