Reversible hyperphagia and obesity in rats with gastric bypass by central MC3/4R blockade

OBJECTIVE: To test the commonly held assumption that gastric bypass surgery lowers body weight because it limits the ability to eat large amounts of food. DESIGN AND METHODS: Central melanocortin signaling was blocked by ICV infusion of the melanocortin-3/4 receptor antagonist SHU9119 for 14 days in rats who’s high-fat diet-induced obesity had been reversed by Roux-en-Y gastric bypass surgery. RESULTS: SHU9119 increased daily food intake (+ 100%), body weight (+30%), and fat mass (+50%) in rats with RYGB, surpassing the presurgical body weight and that of saline-treated sham-operated rats. Doubling of food intake was entirely due to increased meal frequency, but not meal size. After termination of SHU9119, body weight promptly returned to near preinfusion levels. In sham-operated rats, SHU9119 produced even larger increases in food intake and body weight. CONCLUSIONS: RYGB rats do not settle at a lower level of body weight because they cannot eat more food as they can easily double food intake by increasing meal frequency. The reversible obesity suggests that RYGB rats actively defend the lower body weight. However, because both RYGB and sham-operated rats responded to SHU9119, central melanocortin signaling is not the critical mechanism in RYGB rats responsible for this defense.