Role of endogenous ghrelin in the hyperphagia of mice with streptozotocin-induced diabetes.
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.
Center for Gastroenterological Research, Catholitic University of Leuven, 3000 Leuven, Belgium.
J
J
Dong
T L
TL
Peeters
B
B
De Smet
D
D
Moechars
C
C
Delporte
P
P
Vanden Berghe
B
B
Coulie
M
M
Tang
I
I
Depoortere
D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000502:physiology; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D054439:Ghrelin; D005934:Glucagon / Q000097:blood; D006963:Hyperphagia / Q000209:etiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009478:Neuropeptide Y / Q000032:analysis / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology; D036361:Peptide Hormones / Q000097:blood / Q000502:physiology*; D013311:Streptozocin; D000521:alpha-MSH / Q000032:analysis
D001786:Blood Glucose; D054439:Ghrelin; D009478:Neuropeptide Y; D009842:Oligopeptides; D036361:Peptide Hormones; C041048:growth hormone releasing hexapeptide; D000521:alpha-MSH; D013311:Streptozocin; D005934:Glucagon