The effect of the melanocortin agonist, MT-II, on the defended level of body adiposity.

A wide range of experimental evidence implicates a critical role for melanocortin signaling in the control of food intake and body adiposity. Melanocortin receptor agonists such as MT-II potently reduce food intake and body weight, making such agonists potential therapeutics for obesity. The critical concept addressed by the present experiments is whether the homeostatic effects of melanocortin agonists directly regulate food intake or whether the effects on food intake are secondary, with the primary effects being the regulation of body weight and adiposity. To investigate this, we compared the effect of various doses of MT-II given via osmotic minipump for 28 d to alter food intake, body weight, and body fat in dietary-induced obese rats. In addition, before the implantation of the minipump, dietary-induced obese rats were weight reduced by differing amounts using varying levels of food restriction. The results show that in food-restricted rats, MT-II-treated rats consume significantly more calories than those receiving MT-II after ad libitum access to food. More importantly, regardless of the widely differing levels of body fat among the different dietary treatments employed, body fat at the end of the study was determined exclusively by the dose of MT-II, with MT-II-treated rats having less body fat than vehicle-treated rats. These experiments support the hypothesis that melanocortin signaling primarily regulates total body adiposity and that food intake is adjusted as necessary to achieve a specific level of body adiposity.

Two novel paradigms for the simultaneous assessment of conditioned taste aversion and food intake effects of anorexic agents.

The conditioned taste aversion (CTA) is routinely used to assess the aversive consequences of anorexic agents, including potential pharmacological therapies for obesity. In a typical CTA paradigm, rats briefly sampling a novel tastant (e.g., saccharin) are acutely administered with toxin (e.g., lithium chloride, LiCl). After as few as one taste-toxin pairing, rats will reliably avoid the novel tastant. This paradigm is frequently used for the assessment of possible aversive consequences of drugs that are candidates for pharmacological therapies. The degree to which the drug supports development of a CTA is interpreted as an index of its aversive properties. Difficulties with previous work include the inability to assess affects on food intake and CTA simultaneously, particularly during chronic drug administration. We report here two novel CTA paradigms for the assessment of appetitive and aversive consequences of anorexic agents, simultaneously. In the first experiment, animals receive an intraoral infusion of a novel and highly palatable tastant immediately prior to administration of increasing doses of LiCl. In the second experiment, rats were implanted intraperitoneally with osmotic minipumps that chronically delivered a low dose of LiCl for 7 days. LiCl did not affect short or long term food intake in either experiment. However, LiCl did support the development of a CTA in both paradigms. These results suggest that both the appetitive and aversive consequences of anorexic agents can be assessed simultaneously during either acute or chronic drug administration.