Peripheral exendin-4 and peptide YY(3-36) synergistically reduce food intake through different mechanisms in mice

Endocrinology. 2005 Sep;146(9):3748-56. doi: 10.1210/en.2005-0473. Epub 2005 Jun 2.


Glucagon-like peptide-1(7-36NH2) (GLP-1) and peptide YY(3-36NH2) (PYY(3-36NH2)) are cosecreted from the intestine in response to nutrient ingestion. Peripheral administration of GLP-1 or PYY(3-36NH2) decreases food intake (FI) in rodents and humans; however, the exact mechanisms by which these peptides regulate FI remain unclear. Male C57BL/6 mice were injected (ip) with exendin-4(1-39) (Ex4, a GLP-1 receptor agonist) and/or PYY(3-36NH2) (0.03-3 microg), and FI was determined for up to 24 h. Ex4 and PYY(3-36NH2) alone decreased FI by up to 83 and 26%, respectively (P < 0.05-0.001), whereas a combination of the two peptides (0.06 microg Ex4 plus 3 microg PYY(3-36NH2)) further reduced FI for up to 8 h in a synergistic manner (P < 0.05-0.001). Ex4 and/or PYY(3-36NH2) delayed gastric emptying by a maximum of 19% (P < 0.01-0.001); however, there was no significant effect on locomotor activity nor was there induction of taste aversion. Capsaicin pretreatment prevented the inhibitory effect of Ex4 on FI (P < 0.05), but had no effect on the anorexigenic actions of PYY(3-36NH2). Similarly, exendin-4(9-39) (a GLP-1 receptor antagonist) partially abolished Ex4-induced anorexia (P < 0.05), but did not affect the satiation produced by PYY(3-36NH2). Conversely, BIIE0246 (a Y2 receptor antagonist) completely blocked the anorexigenic effects of PYY(3-36NH2) (P < 0.001), but had no effect on Ex4-induced satiety. Thus, Ex4 and PYY(3-36NH2) suppress FI via independent mechanisms involving a GLP-1 receptor-dependent, sensory afferent pathway (Ex4) and a Y2-receptor mediated pathway (PYY(3-36NH2)). These findings suggest that administration of low doses of Ex4 together with PYY(3-36NH2) may increase the suppression of FI without inducing significant side effects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Eating / drug effects*
  • Eating / physiology
  • Exenatide
  • Gastric Emptying / drug effects
  • Gastric Emptying / physiology
  • Injections, Intraperitoneal
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Obesity / drug therapy
  • Obesity / physiopathology
  • Peptide Fragments
  • Peptide YY / pharmacology*
  • Peptides / pharmacology*
  • Satiety Response / drug effects
  • Satiety Response / physiology
  • Venoms / pharmacology*


  • Peptide Fragments
  • Peptides
  • Venoms
  • Peptide YY
  • peptide YY (3-36)
  • Exenatide