Antagonism of
opioid systems (e.g., with
naltrexone) has been explored as an anti-
obesity strategy, and is particularly effective when co-administered with dual inhibitors of
dopamine and
norepinephrine reuptake (e.g.,
bupropion). Previously, we demonstrated that
amylin enhances the food intake lowering and
weight loss effects of neurohormonal (e.g.,
leptin,
cholecystokinin,
melanocortins) and small molecule (e.g.,
phentermine,
sibutramine) agents. Here, we sought to characterize the interaction of
amylin with
naltrexone/
bupropion on energy balance. Wild-type and
amylin knockout mice were similarly responsive to the food intake lowering effects of either
naltrexone (1mg/kg, subcutaneous) or
bupropion (50mg/kg, subcutaneous) suggesting that they act independently of amylinergic systems and could interact additively when given in combination with
amylin. To test this, diet-induced obese rats were treated (for 11 days) with vehicle, rat
amylin (50 μg/kg/d, infused subcutaneously),
naltrexone/
bupropion (1 and 20mg/kg, respectively by twice daily
subcutaneous injection) or their combination. We found that amylin+naltrexone/
bupropion combination
therapy exerted additive effects to reduce cumulative food intake,
body weight and fat mass. In a separate study, the effects of
amylin and
naltrexone/
bupropion administered at the same doses (for 14 days) were compared to a pair-fed group. Although the combination and pair-fed groups lost a similar amount of
body weight, rats treated with the combination lost 68% more fat and better maintained their lean mass. These findings support the strategy of combined
amylin agonism with
opioid and catecholaminergic signaling systems for the treatment of
obesity.