Peripheral exendin-4 and peptide YY3-36 synergistically reduce food intake through different mechanisms in mice

Glucagon-like peptide-1(7-36NH2) (GLP-1) and peptide YY3-36NH2 (PYY3-36NH2) are cosecreted 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 (ip) with exendin-4(1-39) (Ex4, a GLP-1 receptor agonist) and/or PYY3-36NH2 (0.03-3 mu g), 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), whereas a combination of the two peptides (0.06 mu g Ex4 plus 3 mu g 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 pretreatment prevented the inhibitory effect of Ex4 on FI (P < 0.05), but had no effect on the anorexigenic actions of PYY3-36NH2. 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 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.