Role of endogenous ghrelin in the hyperphagia of mice with streptozotocin-induced diabetes

Endocrinology. 2006 Jun;147(6):2634-42. doi: 10.1210/en.2005-1335. Epub 2006 Feb 16.


Ghrelin is an orexigenic peptide involved in the regulation of energy homeostasis. To investigate the role of ghrelin in the hyperphagia associated with uncontrolled streptozotocin-induced diabetes, food intake was followed in diabetic ghrelin knockout (ghrelin(-/-)) and control wild-type (ghrelin(+/+)) mice and diabetic Naval Medical Research Institute noninbred Swiss mice treated with either saline or the ghrelin receptor antagonist, D-Lys3-GH-releasing peptide-6 (D-Lys3-GHRP-6) for 5 d. In diabetic ghrelin(-/-) mice, hyperphagia was attenuated, and the maximal increase in food intake was 50% lower in mutant than in wild-type mice. The increased food intake observed during the light period (1000-1200 h) in ghrelin(+/+) mice was abolished in mutant mice. Diabetic ghrelin(-/-) mice lost 12.4% more body weight than ghrelin(+/+) mice. In diabetic ghrelin(+/+) mice, but not in ghrelin(-/-) mice, the number of neuropeptide Y (NPY)-immunoreactive neurons was significantly increased. Diabetic Naval Medical Research Institute noninbred Swiss mice were hyperphagic and had increased plasma ghrelin levels. Treatment with D-Lys3-GHRP-6 reduced daily food intake by 23% and reversed the increased food intake observed during the light period. The change in the number of NPY- (2.4-fold increase) and alpha-MSH (1.7-fold decrease)-immunoreactive hypothalamic neurons induced by diabetes was normalized by D-Lys3-GHRP-6 treatment. Our results suggest that enhanced NPY and reduced alpha-MSH expression are secondary to the release of ghrelin, which should be considered the underlying trigger of hyperphagia associated with uncontrolled diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arcuate Nucleus of Hypothalamus / physiology
  • Blood Glucose / analysis
  • Body Weight
  • Diabetes Mellitus, Experimental / complications*
  • Ghrelin
  • Glucagon / blood
  • Hyperphagia / etiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neuropeptide Y / analysis
  • Neuropeptide Y / physiology
  • Oligopeptides / pharmacology
  • Peptide Hormones / blood
  • Peptide Hormones / physiology*
  • Streptozocin
  • alpha-MSH / analysis


  • Blood Glucose
  • Ghrelin
  • Neuropeptide Y
  • Oligopeptides
  • Peptide Hormones
  • growth hormone releasing hexapeptide
  • alpha-MSH
  • Streptozocin
  • Glucagon