shu-9119 and Weight-Loss

To test the commonly held assumption that gastric bypass surgery lowers body weight because it limits the ability to eat large amounts of food.. Central melanocortin signaling was blocked by ICV infusion of the melanocortin-3/4 receptor antagonist SHU9119 for 14 days in rats whose high-fat diet-induced obesity had been reversed by Roux-en-Y gastric bypass surgery.. 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.. 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.

Topics: Animals; Body Weight; Diet, High-Fat; Eating; Gastric Bypass; Hyperphagia; Male; Melanocortins; Melanocyte-Stimulating Hormones; Obesity; Rats; Rats, Sprague-Dawley; Receptor, Melanocortin, Type 4; Weight Loss

The cytokine interleukin-1 (IL-1), which mediates many responses to infection and injury, induces anorexia and fever through direct actions in the central nervous system. The melanocortin neuropeptides, such as alpha melanocyte-stimulating hormone (alpha-MSH), reportedly antagonize many actions of IL-1, including fever and anorexia. However, it is unknown whether endogenous melanocortins modulate anorexia induced by IL-1. The objective of the present study was to establish the effect of endogenous melanocortins on IL-1-induced anorexia and fever in the rat. Intracerebroventricular (i.c.v.) injection of IL-1beta caused a significant reduction in food intake and body weight gain, and a rise in core body temperature in conscious rats. Coadministration of the melanocortin-3/4 receptor (MC3/4-R) antagonist, SHU9119, reversed IL-1beta-induced reductions in food intake and body weight, but did not affect the febrile response to IL-1beta. These data suggest IL-1beta may elicit its effects on food intake through the melanocortin system, predominantly via the MC3-R or MC4-R. In contrast, IL-1beta-induced fever does not appear to be mediated or modulated by MC3-R or MC4-R activity.

Topics: alpha-MSH; Animals; Anorexia; Appetite Depressants; Body Temperature; Brain; Eating; Fever; Injections, Intraventricular; Interleukin-1; Kinetics; Male; Melanocyte-Stimulating Hormones; Pyrogens; Rats; Rats, Sprague-Dawley; Receptors, Corticotropin; Receptors, Melanocortin; Weight Loss