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Suppression of food intake by glucagon-like peptide-1 receptor agonists: relative potencies and role of dipeptidyl peptidase-4.

Publication ,  Journal Article
Jessen, L; Aulinger, BA; Hassel, JL; Roy, KJ; Smith, EP; Greer, TM; Woods, SC; Seeley, RJ; D'Alessio, DA
Published in: Endocrinology
December 2012

Administration of the glucagon-like peptide-1 (GLP-1) receptor agonists GLP-1 and exendin-4 (Ex-4) directly into the central nervous system decreases food intake. But although Ex-4 potently suppresses food intake after peripheral administration, the effects of parenteral GLP-1 are variable and not as strong. A plausible explanation for these effects is the rapid inactivation of circulating GLP-1 by dipeptidyl peptidase-4 (DPP-4), an enzyme that does not alter Ex-4 activity. To test this hypothesis, we assessed the relative potency of Ex-4 and GLP-1 under conditions in which DPP-4 activity was reduced. Outbred rats, wild-type mice, and mice with a targeted deletion of DPP-4 (Dpp4(-/-)) were treated with GLP-1 alone or in combination with the DPP-4 inhibitor vildagliptin, Ex-4, or saline, and food intake was measured. GLP-1 alone, even at high doses, did not affect feeding in wild-type mice or rats but did reduce food intake when combined with vildagliptin or given to Dpp4(-/-) mice. Despite plasma clearance similar to DPP-4-protected GLP-1, equimolar Ex-4 caused greater anorexia than vildagliptin plus GLP-1. To determine whether supraphysiological levels of endogenous GLP-1 would suppress food intake if protected from DPP-4, rats with Roux-en-Y gastric bypass and significantly elevated postprandial plasma GLP-1 received vildagliptin or saline. Despite 5-fold greater postprandial GLP-1 in these animals, vildagliptin did not affect food intake in Roux-en-Y gastric bypass rats. Thus, in both mice and rats, peripheral GLP-1 reduces food intake significantly less than Ex-4, even when protected from DPP-4. These findings suggest distinct potencies of GLP-1 receptor agonists on food intake that cannot be explained by plasma pharmacokinetics.

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Published In

Endocrinology

DOI

EISSN

1945-7170

Publication Date

December 2012

Volume

153

Issue

12

Start / End Page

5735 / 5745

Location

United States

Related Subject Headings

  • Vildagliptin
  • Receptors, Glucagon
  • Rats, Long-Evans
  • Rats
  • Pyrrolidines
  • Nitriles
  • Models, Biological
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice
 

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Jessen, L., Aulinger, B. A., Hassel, J. L., Roy, K. J., Smith, E. P., Greer, T. M., … D’Alessio, D. A. (2012). Suppression of food intake by glucagon-like peptide-1 receptor agonists: relative potencies and role of dipeptidyl peptidase-4. Endocrinology, 153(12), 5735–5745. https://doi.org/10.1210/en.2012-1358
Jessen, Lene, Benedikt A. Aulinger, Jonathan L. Hassel, Kyle J. Roy, Eric P. Smith, Todd M. Greer, Stephen C. Woods, Randy J. Seeley, and David A. D’Alessio. “Suppression of food intake by glucagon-like peptide-1 receptor agonists: relative potencies and role of dipeptidyl peptidase-4.Endocrinology 153, no. 12 (December 2012): 5735–45. https://doi.org/10.1210/en.2012-1358.
Jessen L, Aulinger BA, Hassel JL, Roy KJ, Smith EP, Greer TM, et al. Suppression of food intake by glucagon-like peptide-1 receptor agonists: relative potencies and role of dipeptidyl peptidase-4. Endocrinology. 2012 Dec;153(12):5735–45.
Jessen, Lene, et al. “Suppression of food intake by glucagon-like peptide-1 receptor agonists: relative potencies and role of dipeptidyl peptidase-4.Endocrinology, vol. 153, no. 12, Dec. 2012, pp. 5735–45. Pubmed, doi:10.1210/en.2012-1358.
Jessen L, Aulinger BA, Hassel JL, Roy KJ, Smith EP, Greer TM, Woods SC, Seeley RJ, D’Alessio DA. Suppression of food intake by glucagon-like peptide-1 receptor agonists: relative potencies and role of dipeptidyl peptidase-4. Endocrinology. 2012 Dec;153(12):5735–5745.
Journal cover image

Published In

Endocrinology

DOI

EISSN

1945-7170

Publication Date

December 2012

Volume

153

Issue

12

Start / End Page

5735 / 5745

Location

United States

Related Subject Headings

  • Vildagliptin
  • Receptors, Glucagon
  • Rats, Long-Evans
  • Rats
  • Pyrrolidines
  • Nitriles
  • Models, Biological
  • Mice, Transgenic
  • Mice, Inbred C57BL
  • Mice