Both Acyl and Des-Acyl Ghrelin Regulate Adiposity and Glucose Metabolism via Central Nervous System Ghrelin Receptors
| Autor: | Heike Biebermann, Darleen A. Sandoval, Kristy M. Heppner, Kirk M. Habegger, David L. Smiley, Diego Perez-Tilve, Anne Müller, Nickki Ottaway, Paul T. Pfluger, Matthias H. Tschöp, Carolin L. Piechowski, Richard D. DiMarchi, Stephanie Sisley |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Agonist
Central Nervous System medicine.medical_specialty medicine.drug_class Endocrinology Diabetes and Metabolism medicine.medical_treatment 030209 endocrinology & metabolism Endogeny Carbohydrate metabolism Biology 03 medical and health sciences Mice 0302 clinical medicine Growth hormone secretagogue Internal medicine Internal Medicine medicine Animals Humans Receptor Receptors Ghrelin 030304 developmental biology Adiposity 0303 health sciences urogenital system Insulin digestive oral and skin physiology Biological activity Ghrelin Endocrinology Glucose HEK293 Cells Infusions Intraventricular Metabolism lipids (amino acids peptides and proteins) |
| Zdroj: | Diabetes; Vol 63 Diabetes |
| ISSN: | 0012-1797 |
| DOI: | 10.2337/db13-0414 |
| Popis: | Growth hormone secretagogue receptors (GHSRs) in the central nervous system (CNS) mediate hyperphagia and adiposity induced by acyl ghrelin (AG). Evidence suggests that des-AG (dAG) has biological activity through GHSR-independent mechanisms. We combined in vitro and in vivo approaches to test possible GHSR-mediated biological activity of dAG. Both AG (100 nmol/L) and dAG (100 nmol/L) significantly increased inositol triphosphate formation in human embryonic kidney-293 cells transfected with human GHSR. As expected, intracerebroventricular infusion of AG in mice increased fat mass (FM), in comparison with the saline-infused controls. Intracerebroventricular dAG also increased FM at the highest dose tested (5 nmol/day). Chronic intracerebroventricular infusion of AG or dAG increased glucose-stimulated insulin secretion (GSIS). Subcutaneously infused AG regulated FM and GSIS in comparison with saline-infused control mice, whereas dAG failed to regulate these parameters even with doses that were efficacious when delivered intracerebroventricularly. Furthermore, intracerebroventricular dAG failed to regulate FM and induce hyperinsulinemia in GHSR-deficient (Ghsr−/−) mice. In addition, a hyperinsulinemic-euglycemic clamp suggests that intracerebroventricular dAG impairs glucose clearance without affecting endogenous glucose production. Together, these data demonstrate that dAG is an agonist of GHSR and regulates body adiposity and peripheral glucose metabolism through a CNS GHSR-dependent mechanism. |
| Databáze: | OpenAIRE |
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