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

Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) are cosecreted from the intestine in response to nutrient ingestion. Peripheral administration of GLP-1 or PYY 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 (Ex4, a GLP-1 receptor agonist) and/or PYY (0.03–3 g), and FI was determined for up to 24 h. Ex4 and PYY alone decreased FI by up to 83 and 26%, respectively (P < 0.05–0.001), whereas a combination of the two peptides (0.06 g Ex4 plus 3 g PYY) further reduced FI for up to 8 h in a synergistic manner (P < 0.05–0.001). Ex4 and/or PYY 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. Similarly, exendin-4 (a GLP-1 receptor antagonist) partially abolished Ex4-induced anorexia (P < 0.05), but did not affect the satiation produced by PYY. Conversely, BIIE0246 (a Y2 receptor antagonist) completely blocked the anorexigenic effects of PYY (P < 0.001), but had no effect on Ex4-induced satiety. Thus, Ex4 and PYY suppress FI via independent mechanisms involving a GLP-1 receptor-dependent, sensory afferent pathway (Ex4) and a Y2-receptor mediated pathway (PYY). These findings suggest that administration of low doses of Ex4 together with PYY may increase the suppression of FI without inducing significant side effects. (Endocrinology 146: 3748–3756, 2005)