The melanocortin antagonist AgRP (83-132) increases appetitive responding for a fat, but not a carbohydrate, reinforcer.

Consumption of a diet high in fat is a risk factor for a number of health problems, including obesity, type 2 diabetes and cardiovascular disease. Considerable pharmacological, genetic, and molecular evidence suggests that the hypothalamic melanocortin system plays a critical role in the control of food intake and body weight and, specifically, in fat ingestion. Administration of a melanocortin antagonist, agouti-related peptide (AgRP) (83-132) selectively increases intake of pure fat and high-fat mixed diets. Here, we examined possible mechanisms for this fat-specific effect of AgRP (83-132). In Experiment 1, we determined that intracerebroventricular administration of AgRP (83-132) selectively increased operant responding for a peanut oil, but not a sucrose, reinforcer when tested under a progressive ratio schedule. Experiment 2 employed a Pavlovian conditioning paradigm, in which icv AgRP enhanced appetitive responding toward stimuli that had previously been paired with peanut oil and reduced responding toward stimuli previously paired with sucrose, in the absence of consumption of either macronutrient. Finally, in Experiment 3, we tested the hypothesis that the MC system acts in anticipation of a fat consumption and found that hypothalamic AgRP mRNA was slightly, though not significantly, elevated in an environment predicting fat availability relative to one predicting carbohydrate availability. Collectively, these data indicate that, in addition to increasing free intake of dietary fats, AgRP (83-132) promotes responding for the opportunity to consume a fat reinforcer, as well as appetitive responding to fat-paired stimuli in the absence of ingestive stimulation. These results suggest a possible role for AgRP in the increased fat intake associated with obesity.