Both Acyl and Des-Acyl Ghrelin Regulate Adiposity and Glucose Metabolism via Central Nervous System Ghrelin Receptors

  1. Diego Perez-Tilve1
  1. 1Department of Medicine, Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH
  2. 2Institute of Experimental Pediatric Endocrinology, Charité-Universitätsmedizin Berlin, Berlin, Germany
  3. 3Cincinnati Children’s Hospital Medical Center, Cincinnati, OH
  4. 4Department of Chemistry, Indiana University, Bloomington, IN
  5. 5Institute for Diabetes and Obesity, Hemholtz Zentrum München and Technische Universität München, Munich, Germany
  1. Corresponding author: Diego Perez-Tilve, pereztdo{at}


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.

  • Received March 13, 2013.
  • Accepted September 18, 2013.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See for details.

| Table of Contents

This Article

  1. Diabetes vol. 63 no. 1 122-131
  1. All Versions of this Article:
    1. db13-0414v1
    2. 63/1/122 most recent