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Peripheral Exendin-4 and Peptide YY^3–36 Synergistically Reduce Food Intake through Different Mechanisms in Mice

Departments of Physiology (T.T., Y.A., S.S., P.L.B.) and Medicine (D.J.D., P.L.B.) and Banting and Best Diabetes Centre (D.J.D.), University of Toronto, Toronto, Ontario, Canada M5S 1A8; and Ottawa Health Research Institute (Y.A.), Ottawa, Ontario, Canada K1Y 4E9

Address all correspondence and requests for reprints to: Dr. Patricia L. Brubaker, Room 3366, Medical Sciences Building, University of Toronto, 1 King’s College Circle, Toronto, Ontario, Canada M5S 1A8. E-mail: p.brubaker{at}utoronto.ca.

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 µg), 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 µg Ex4 plus 3 µg 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.

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