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Submitted on April 20, 2005
Accepted on May 23, 2005
Departments of Physiology and Medicine and the Banting and Best Diabetes Centre, University of Toronto, Toronto, ON, Canada, and Ottawa Health Research Institute, Ottawa, ON, Canada
* To whom correspondence should be addressed. E-mail: p.brubaker{at}utoronto.ca.
Glucagon-like peptide-17-36NH2 (GLP-1) and peptide YY3-36NH2 (PYY3-36NH2) are co-secreted from the intestine in response to nutrient ingestion. Peripheral administration of GLP-1 or PYY3-36NH2 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 (i.p.) with exendin-4 (1-39) (Ex4: a GLP-1 receptor agonist) and/or PYY3-36NH2 (0.03-3 µg), and FI was determined for up to 24 h. Ex4 and PYY3-36NH2 alone decreased FI by up to 83 and 26%, respectively (P < 0.05-0.001), while a combination of the two peptides (0.06 µg Ex4 plus 3 µg PYY3-36NH2) further reduced FI for up to 8 h in a synergistic manner (P < 0.05-0.001). Ex4 and/or PYY3-36NH2 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 pre-treatment prevented the inhibitory effect of Ex4 on FI (P < 0.05), but had no effect on the anorexigenic actions of PYY3-36NH2. Similarly, exendin-49-39 (a GLP-1 receptor antagonist) partially abolished Ex4-induced anorexia (P < 0.05), but did not affect the satiation produced by PYY3-36NH2. Conversely, BIIE0246 (a Y2 receptor antagonist) completely blocked the anorexigenic effects of PYY3-36NH2 (P < 0.001), but had no effect on Ex4-induced satiety. Thus, Ex4 and PYY3-36NH2 suppress FI via independent mechanisms involving a GLP-1 receptor-dependent, sensory afferent pathway (Ex4) and a Y2-receptor mediated pathway (PYY3-36NH2). These findings suggest that administration of low doses of Ex4 together with PYY3-36NH2 may increase the suppression of FI without inducing significant side effects.
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