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Combination Therapy with Amylin and Peptide YY[3–36] in Obese Rodents: Anorexigenic Synergy and Weight Loss Additivity

Amylin Pharmaceuticals, Inc., San Diego, California 92121

Address all correspondence to: Jonathan Roth, Ph.D., Amylin Pharmaceuticals, Inc., 9360 Towne Centre Drive, San Diego, California 92121. E-mail: jonathan.roth{at}amylin.com.

Circulating levels of the pancreatic ß-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 µg/kg) plus PYY[3–36] (1000 µg/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 µg/kg·d) and PYY[3–36] (0, 200, 400 µg/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.

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