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.
Dong
J
J
Center for Gastroenterological Research, Catholitic University of Leuven, 3000 Leuven, Belgium.
Peeters
T L
TL
De Smet
B
B
Moechars
D
D
Delporte
C
C
Vanden Berghe
P
P
Coulie
B
B
Tang
M
M
Depoortere
I
I
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