Role of Endogenous Ghrelin in the Hyperphagia of Mice with Streptozotocin-Induced Diabetes

• Published in: Endocrinology (Philadelphia) Vol. 147; no. 6; pp. 2634 - 2642
• Main Authors: Dong, J, Peeters, T. L, De Smet, B, Moechars, D, Delporte, C, Vanden Berghe, P, Coulie, B, Tang, M, Depoortere, I
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01.06.2006
• Subjects: alpha-MSH - analysis; Animals; Arcuate Nucleus of Hypothalamus - physiology; Biological and medical sciences; Blood Glucose - analysis; Body Weight; Diabetes Mellitus, Experimental - complications; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fundamental and applied biological sciences. Psychology; Ghrelin; Glucagon - blood; Hyperphagia - etiology; Male; Medical sciences; Mice; Mice, Inbred C57BL; Neuropeptide Y - analysis; Neuropeptide Y - physiology; Oligopeptides - pharmacology; Peptide Hormones - blood; Peptide Hormones - physiology; Streptozocin; Vertebrates: endocrinology; Endocrinopathy; Vertebrata; Feeding behavior; Mammalia; Endogenous; Mouse; Ghrelin; Animal; Diabetes mellitus; Rodentia; Streptozotocin; Hyperphagia
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2005-1335

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 α-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 α-MSH expression are secondary to the release of ghrelin, which should be considered the underlying trigger of hyperphagia associated with uncontrolled diabetes.