Chronic intracerebroventricular administration of recombinant CART(42-89) peptide inhibits food intake and causes weight loss in lean and obese Zucker (fa/fa) rats

Objective: Hypothalamic neuropeptide CART (cocaine-amphetamine-regulated tr anscript) is a leptin-dependent endogenous satiety factor in the rat, and s ingle central injections of recombinant CART(42-89) lowers food intake in r ats and mice. To assess the potential role of CART as a long-term regulator of food intake, we investigated the effects of continuous infusion of reco mbinant CART(42-89! on food consumption and body weight. Research Methods and Procedures: Two doses of CART(42-89) were tested: 12 o r 4.8 mug/d. Adult male, both lean (+/?) and Zucker (fa/fa) obese, rats wer e equipped with intracerebroventricular cannulae in the right lateral ventr icle. The cannulae were connected to subcutaneously placed osmotic mini-pum ps. Pumps were filled with either CART(42-89) or vehicle (50 mM phosphate-b uffered saline, pH 7.4). The pumps delivered a continuous infusion of CART( 42-89) or vehicle, and food intake and body weight were followed for 10 day s (12 mug/d) or 7 days (4.8 mug/d). Animals given the low dose had the pump removed on Day 7, and from half of the,group, trunk blood was collected af ter decapitation, whereas the other half of the group had their mini-pumps removed and were followed for another 7 days before being decapitated. Results: Animals receiving the high doses displayed overt motor disturbance s, whereas the low dose was devoid of such behavioral side effects. Both do ses significantly lowered food intake with maximal effect on days 3 to 5 of the infusion period. The high dose of CART decreased body weight of normal animals to 85% of initial weight at days 3 to 5? whereas the weight of Zuc ker (fa/fa) obese rats dropped to 95% of the initial weight. In animals rec eiving 4.8 mug/d, moderate effects on body weight were seen between days 4 and 6 of the treatment period, but soon after termination of the treatment animals regained lost weight. To assess the biological activity of the cont ents of the osmotic mini-pumps, the pumps were removed from the subcutaneou s implantation site, and 5 muL of their contents were injected intracerebro ventricularly to naive animals kept on a restricted feeding schedule. The c ontent of pumps from animals receiving 4.8 mug/d of CART(42-89) potently in hibited food intake, confirming full biological activity despite being kept for 7 days at body temperature. Discussion: Due to obvious effects on motor behavior, it is impossible with certainty to conclude that the observed effects on feeding and body weight are primary interference with satiety centers or secondary to effects on l ocomotor pathways. Also, the present experiments suggest that hypothalamic appetite-regulating neurons are subject to pharmacological desensitization upon prolonged exposure to CART peptide. The underlying mechanism of such d esensitization is as yet unknown.