Differences in the Central Anorectic Effects of Glucagon-Like Peptide-1 and Exendin-4 in Rats

  1. Jason G. Barrera1,
  2. David A. D'Alessio2,
  3. Daniel J. Drucker3,
  4. Stephen C. Woods1 and
  5. Randy J. Seeley1
  1. 1Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio;
  2. 2Department of Internal Medicine, University of Cincinnati, Cincinnati, Ohio;
  3. 3Department of Medicine, Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
  1. Corresponding author: Jason G. Barrera, barrerjg{at}email.uc.edu.

Abstract

OBJECTIVE Glucagon-like peptide (GLP)-1 is a regulatory peptide synthesized in the gut and the brain that plays an important role in the regulation of food intake. Both GLP-1 and exendin (Ex)-4, a long-acting GLP-1 receptor (GLP-1r) agonist, reduce food intake when administered intracerebroventricularly, whereas Ex4 is much more potent at suppressing food intake when given peripherally. It has generally been hypothesized that this difference is due to the relative pharmacokinetic profiles of GLP-1 and Ex4, but it is possible that the two peptides control feeding via distinct mechanisms.

RESEARCH DESIGN AND METHODS In this study, the anorectic effects of intracerebroventricular GLP-1 and Ex4, and the sensitivity of these effects to GLP-1r antagonism, were compared in rats. In addition, the GLP-1r dependence of the anorectic effect of intracerebroventricular Ex4 was assessed in GLP-1r−/− mice.

RESULTS Intracerebroventricular Ex4 was 100-fold more potent than GLP-1 at reducing food intake, and this effect was insensitive to GLP-1r antagonism. However, GLP-1r antagonists completely blocked the anorectic effect of intraperitoneal Ex4. Despite the insensitivity of intracerebroventricular Ex4 to GLP-1r antagonism, intracerebroventricular Ex4 failed to reduce food intake in GLP-1r−/− mice.

CONCLUSIONS These data suggest that although GLP-1rs are required for the actions of Ex4, there appear to be key differences in how GLP-1 and Ex4 interact with central nervous system GLP-1r and in how Ex4 interacts with GLP-1r in the brain versus the periphery. A better understanding of these unique differences may lead to expansion and/or improvement of GLP-1–based therapies for type 2 diabetes and obesity.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Received February 24, 2009.
    • Accepted August 26, 2009.
| Table of Contents

This Article

  1. Diabetes vol. 58 no. 12 2820-2827
  1. All Versions of this Article:
    1. db09-0281v1
    2. 58/12/2820 most recent