Combination therapy with amylin and PYY(3–36) in diet-induced obese rats: A response surface analysis.

Abstract

Amylin (from pancreatic B-cells), and PYY(3–36) (from ileal L-cells) are both released following a meal and act as short-term satiety signals. Peripheral administration of the individual peptide hormones has been shown to reduce food intake (FI) and body weight (BW) in rodent models. We recently demonstrated that the combination of amylin and PYY(3–36) appeared to exert additive FI- and BW-lowering effects in diet-induced obese (DIO) rodents. In the present study, we extended these findings by using a 4×3 factorial design (n=5/group) to define the interaction of a range of doses of amylin (0, 4, 20, 100 μg/kg/d) and PYY(3–36) (0, 200, 400 μg/kg/d) on FI and BW loss following 2-week subcutaneous (SC) infusion in DIO rats. This design enabled us to formally test for statistical additivity or synergy using Response Surface Methodology (RSM), where p-values less than 0.05 indicate synergy and non-significant p-values suggest additivity. At 2 weeks, the RSM showed that (1) cumulative FI (% vehicle-corrected±SEM) was synergistically reduced across the combinations (p=0.022) by up to 54.7±1.1% and, (2) BW (% vehicle corrected±SEM) was additively reduced (p=0.27) across the combinations by up to 15.6±0.9%. Our results formally confirm that in DIO rats, amylin and PYY(3–36) have additive effects for BW loss, mediated in part via a synergistic suppression of food intake. These preclinical findings point to the need for further studies to investigate the potential utility of integrated neurohormonal approaches for the treatment of obesity.