Circulating levels of the pancreatic beta-cell
peptide hormone amylin and the gut
peptide PYY[3-36] increase after nutrient ingestion. Both have been implicated as short-term signals of meal termination with anorexigenic and weight-reducing effects. However, their combined effects are unknown. We report that the combination of
amylin and PYY[3-36] elicited greater anorexigenic and weight-reducing effects than either
peptide alone. In high-fat-fed rats, a single ip injection of
amylin (10 microg/kg) plus PYY[3-36] (1000 microg/kg) reduced food intake for 24 h (P < 0.05 vs. vehicle), whereas the anorexigenic effects of either PYY[3-36] or
amylin alone began to diminish 6 h after injection. These anorexigenic effects were dissociable from changes in locomotor activity.
Subcutaneous infusion of
amylin plus PYY[3-36] for 14 d suppressed food intake and
body weight to a greater extent than either agent alone in both rat and mouse diet-induced
obesity (DIO) models (P < 0.05). In DIO-prone rats, 24-h metabolic rate was maintained despite
weight loss, and
amylin plus PYY[3-36] (but not monotherapy) increased 24-h fat oxidation (P < 0.05 vs. vehicle). Finally, a 4 x 3 factorial design was used to formally describe the interaction between
amylin and PYY[3-36]. DIO-prone rats were treated with
amylin (0, 4, 20, and 100 microg/kg.d) and PYY[3-36] (0, 200, 400 microg/kg.d) alone and in combination for 14 d. Statistical analyses revealed that food intake suppression with
amylin plus PYY[3-36] treatment was synergistic, whereas
body weight reduction was additive. Collectively, these observations highlight the importance of studying
peptide hormones in combination and suggest that integrated neurohormonal approaches may hold promise as treatments for
obesity.