Leptin-mediated hypothalamic pathway of cholecystokinin (CCK-8) to regulate body weight in free-feeding rats
Leptin-mediated hypothalamic pathway of cholecystokinin (CCK-8) to regulate body weight in free-feeding rats
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DOI：
10.1210/en.2007-1286
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发表时间：
2008-04-01
期刊：
影响因子：
4.8
通讯作者：
Ruiz-Gayo, Mariano
中科院分区：
文献类型：
--
作者：
Merino, Beatriz;Cano, Victoria;Ruiz-Gayo, Mariano
体重的调节是中枢和外周不同激素系统相互作用的结果。本研究的目的是表征胆囊收缩素（CCK）参与BW和能量平衡调节。在自由饲养大鼠中，我们已经表征了CCK-8对1）食物摄入、BW和肥胖; 2）骨骼肌代谢; 3）下丘脑弓状核内的瘦素信号通路;和4）瘦素脑屏障的渗透性的影响。我们在这里证明CCK-8通过部分依赖于中枢瘦素途径的机制急性降低BW，基于以下结果：1）CCK的作用在缺乏功能性瘦素受体的大鼠中较弱（Zucker fa/fa），2）CCK-8促进瘦素从外周循环到脑脊液（CSF）的摄取，3）CCK组大鼠CSF中瘦素浓度在体重损失较大的动物中升高更明显; 4）CCK激活了下丘脑中的瘦素信号通路以及骨骼肌中AMP激活的蛋白激酶的磷酸化。我们还认为，体重的增加可能与个体对CCK作用的敏感性有关，因为我们观察到，在用这种激素治疗的动物中，体重的增加与CSF中的瘦素浓度呈负相关。我们的数据表明，CCK对能量平衡有负面影响，并表明CCK促进瘦素进入下丘脑区域，从而使瘦素作用于参与BW控制的下丘脑靶点。
Regulation of body weight (BW) results from the interplay between different hormonal systems acting at central and peripheral level. This study aims at characterizing the involvement of cholecystokinin (CCK) in BW and energy balance regulation. We have characterized, in free-feeding rats, the effect of CCK-8 on 1) food intake, BW, and adiposity; 2) skeletal muscle metabolism; 3) leptin signaling pathway within the arcuate nucleus of the hypothalamus; and 4) the permeability of brain barriers to leptin. We demonstrate here that CCK-8 acutely decreases BW by a mechanism partially dependent on central leptin pathways, based on the following results: 1) the effect of CCK was less intense in rats lacking functional leptin receptors (Zucker fa/fa), 2) CCK-8 facilitated the uptake of leptin from peripheral circulation to cerebrospinal fluid (CSF), 3) the concentration of leptin in CSF of rats receiving CCK was more elevated in those animals showing higher loss of BW, and 4) CCK activated leptin signaling pathways within the hypothalamus as well as phosphorylation of AMP-activated protein kinase in skeletal muscle. We also suggest that gain of BW may be linked to individual susceptibility to the effect of CCK, because we observed that in animals treated with this hormone, the increase of BW negatively correlated with leptin concentration within the CSF. Our data show that CCK has a negative impact on energy balance and suggest that CCK facilitates the access of leptin to hypothalamic areas, thus allowing leptin to act on hypothalamic targets involved in BW control.