Multi-hormonal weight loss combinations in diet-induced obese rats: Therapeutic potential of cholecystokinin?

Cholecystokinin (CCK) acutely synergizes with amylin to suppress food intake in lean mice. To extend on these findings, the present studies sought to identify neural correlates for the interaction of amylin and CCK, as well as further understand the therapeutic potential of CCK-based combinations in obesity. First, c-Fos activation was assessed in various brain nuclei after a single intraperitoneal injection of amylin (5 mu g/kg) and/or CCK (5 mu g/kg). Amylin and CCK additively increased c-Fos within the area postrema (AP), predominantly in noradrenergic (e.g., dopamine-beta-hydroxylase-containing) cells. Next, amylin (100 or 300 mu g/kg/d) and/or CCK (100 or 300 mu g/kg/d) were subcutaneously infused for 7 days in diet-induced obese (DIO) rats. Amylin treatment of DID rats for 7 days induced significant body weight loss. CCK, while ineffective alone, significantly enhanced body weight loss when co-administered with the higher dose of amylin. Finally, the addition of CCK (300 mu g/kg/d) to leptin (125 mu g/kg/d), and to the combination of amylin (50 mu g/kg/d) and leptin (125 mu g/kg/d), was also explored in DIO rats via sustained subcutaneous infusion for 14 days. Infusion of amylin/leptin/CCK for 14 days exerted significantly greater body weight loss, inhibition of food intake, and reduction in adiposity compared to amylin/leptin treatment alone in DIO rats. However, co-infusion of CCK and leptin was an ineffective weight loss regimen in this model. Whereas CCK agonism alone is ineffective at eliciting or maintaining weight loss, it durably augmented the food intake and body weight-lowering effects of amylin and amylin/leptin in a relevant disease model, and when combined with amylin, cooperatively activated neurons within the caudal brainstem. (C) 2010 Elsevier Inc. All rights reserved.