Chronic intracerebroventricular administration of recombinant CART(42-89) peptide inhibits food intake and causes weight loss in lean and obese Zucker (fa/fa) rats
Chronic intracerebroventricular administration of recombinant CART(42-89) peptide inhibits food intake and causes weight loss in lean and obese Zucker (fa/fa) rats
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DOI：
10.1038/oby.2000.76
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发表时间：
2000-11-01
期刊：
影响因子：
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通讯作者：
Kristensen, P
中科院分区：
文献类型：
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作者：
Larsen, PJ;Vrang, N;Kristensen, P
目的：下丘脑神经肽CART（cocaine-amphetamine regulated transcript）是大鼠瘦素依赖的内源性饱足因子，单次中央注射重组CART（42-89）可降低大鼠和小鼠的食物摄取量。为了评估CART作为食物摄入长期调节剂的潜在作用，我们研究了持续输注重组CART的效果(42-89！食物消耗和体重的关系。研究方法和步骤：试验两种剂量的CART(42-89): 12杯或4.8杯/d。成年雄性，瘦（+/?）和Zucker （fa/fa）肥胖大鼠，右侧脑室置入脑室内插管。套管连接到皮下放置的渗透微型泵。泵内填充CART（42-89）或载药（50 mM磷酸盐缓冲盐水，pH 7.4）。泵连续输注CART（42-89）或车辆，随访10天（12马克杯/天）或7天（4.8马克杯/天）的食物摄入量和体重。给予低剂量的动物在第7天移除泵，其中一半的动物在斩首后采集主干血，而另一半的动物在被斩首前移除其微型泵，并被随访7天。结果：接受高剂量的动物表现出明显的运动障碍，而低剂量的动物则没有这种行为副作用。两种剂量都显著降低了食物摄入量，在输注期的第3至5天效果最大。高剂量CART使正常动物的体重在第3 ~ 5天降至初始体重的85%。而Zucker肥胖大鼠的体重（fa/fa）降至初始体重的95%。在每天服用4.8杯的动物中，在治疗期的第4天至第6天，体重得到了适度的影响，但在治疗结束后不久，动物的体重又恢复了下降。为了评估渗透微型泵内容物的生物活性，将泵从皮下植入部位取出，并将其内容物5mul注射到限制喂养的幼稚动物脑室内。接受4.8杯/d CART的动物的泵的含量（42-89）有效地抑制了食物摄入，尽管在体温下保存了7天，但仍证实了充分的生物活性。讨论：由于对运动行为有明显的影响，因此不可能肯定地得出结论，观察到的对摄食和体重的影响是对饱腹感中心的主要干扰，还是对运动通路的影响是次要的。此外，本实验表明下丘脑食欲调节神经元在长时间暴露于CART肽后会发生药理学脱敏。这种脱敏的潜在机制尚不清楚。
Objective: Hypothalamic neuropeptide CART (cocaine-amphetamine-regulated transcript) is a leptin-dependent endogenous satiety factor in the rat, and single central injections of recombinant CART(42-89) lowers food intake in rats 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 recombinant CART(42-89! on food consumption and body weight.Research Methods and Procedures: Two doses of CART(42-89) were tested: 12 or 4.8 mug/d. Adult male, both lean (+/?) and Zucker (fa/fa) obese, rats were equipped with intracerebroventricular cannulae in the right lateral ventricle. The cannulae were connected to subcutaneously placed osmotic mini-pumps. Pumps were filled with either CART(42-89) or vehicle (50 mM phosphate-buffered 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 days (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 after 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 disturbances, whereas the low dose was devoid of such behavioral side effects. Both doses 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 Zucker (fa/fa) obese rats dropped to 95% of the initial weight. In animals receiving 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 contents of the osmotic mini-pumps, the pumps were removed from the subcutaneous implantation site, and 5 muL of their contents were injected intracerebroventricularly to naive animals kept on a restricted feeding schedule. The content of pumps from animals receiving 4.8 mug/d of CART(42-89) potently inhibited 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 locomotor 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 desensitization is as yet unknown.