Hypothalamic, metabolic, and behavioral responses to pharmacological inhibition of CNS melanocortin signaling in rats
Hypothalamic, metabolic, and behavioral responses to pharmacological inhibition of CNS melanocortin signaling in rats
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DOI：
10.1523/jneurosci.21-10-03639.2001
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发表时间：
2001-05-15
影响因子：
5.3
通讯作者：
van Dijk, G
中科院分区：
文献类型：
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作者：
Adage, T;Scheurink, AJW;van Dijk, G
CNS黑皮质素（MC）系统被认为是瘦素的中枢作用的介体，CNS MC系统的活性降低促进啮齿动物和人类的肥胖。由于CNS MC受体的激活对自主神经流出和代谢有直接影响，我们假设食物摄入非依赖性机制有助于通过药物阻断脑中MC受体诱导的肥胖症的发展，并且已知调节体重增加的下丘脑神经肽能系统的变化[i.例如，促肾上腺皮质激素释放激素（CRH）、可卡因-苯丙胺相关转录物（CART）、阿黑皮素原（POMC）和神经肽Y（NPY）]将触发该效应。相对于溶剂处理的对照组，第三次侧脑室（i3 vt）给药MC受体拮抗剂SHU 9119 11天使大鼠的摄食量和饮水量加倍（接近治疗结束时）和体重增加（类似于14%）和脂肪含量（与90%相似），肝糖原含量（类似于40%）和血浆胆固醇水平（类似于48%）、胰岛素（类似于259%）、胰高血糖素（类似于80%）和瘦素（类似于490%），而自发运动活动和体温降低。将i3 vtSHU 9119处理的动物与i3 vt赋形剂处理的对照配对喂养使胰岛素、胰高血糖素和肝糖原含量的血浆水平正常化，但仅部分逆转了血浆胆固醇（类似于31%）和瘦素（类似于104%）以及体脂含量（类似于27%）的升高.由i3 vtSHU 9119诱导的体温和自发活动的降低不被配对喂养逆转，而是更明显。所发现的效应均不能用化合物的外周作用来解释。尽管在整个弓状神经解剖学范围内缺乏神经肽表达反应，但仍发生了肥胖效应。例如，CART、POMC和NPY）和室旁（i.例如，CRH）下丘脑。结果表明，降低活性的中枢神经系统MC途径促进脂肪沉积通过两个食物摄入依赖性和非依赖性机制。
The CNS melanocortin (MC) system is implicated as a mediator of the central effects of leptin, and reduced activity of the CNS MC system promotes obesity in both rodents and humans. Because activation of CNS MC receptors has direct effects on autonomic outflow and metabolism, we hypothesized that food intake- independent mechanisms contribute to development of obesity induced by pharmacological blockade of MC receptors in the brain and that changes in hypothalamic neuropeptidergic systems known to regulate weight gain [i. e., corticotropin-releasing hormone (CRH), cocaine- amphetamine- related transcript (CART), proopiomelanocortin (POMC), and neuropeptide Y (NPY)] would trigger this effect. Relative to vehicle- treated controls, third intracerebroventricular (i3vt) administration of the MC receptor antagonist SHU9119 to rats for 11 d doubled food and water intake (toward the end of treatment) and increased body weight (similar to 14%) and fat content (similar to 90%), hepatic glycogen content (similar to 40%), and plasma levels of cholesterol (similar to 48%), insulin (similar to 259%), glucagon (similar to 80%), and leptin (similar to 490%), whereas spontaneous locomotor activity and body temperature were reduced. Pair- feeding of i3vt SHU9119- treated animals to i3vt vehicle- treated controls normalized plasma levels of insulin, glucagon, and hepatic glycogen content, but only partially reversed the elevations of plasma cholesterol (similar to 31%) and leptin (similar to 104%) and body fat content (similar to 27%). Reductions in body temperature and locomotor activity induced by i3vt SHU9119 were not reversed by pair feeding, but rather were more pronounced. None of the effects found can be explained by peripheral action of the compound. The obesity effects occurred despite a lack in neuropeptide expression responses in the neuroanatomical range selected across the arcuate (i. e., CART, POMC, and NPY) and paraventricular (i. e., CRH) hypothalamus. The results indicate that reduced activity of the CNS MC pathway promotes fat deposition via both food intake- dependent and -independent mechanisms.