Intracellular interplay between cholecystokinin and leptin signalling for satiety control in rats
Intracellular interplay between cholecystokinin and leptin signalling for satiety control in rats
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DOI：
10.1038/s41598-020-69035-6
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发表时间：
2020-07-20
影响因子：
4.6
通讯作者：
Ikeda，Masayuki
中科院分区：
文献类型：
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作者：
Koizumi，Hayato;Mohammad，Shahid;Ikeda，Masayuki
胆囊收缩素（cholestokinin，CCK）和瘦素（leptin）都是控制饱腹感的肽，但它们之间的相互作用尚不清楚。在这里，我们使用体外和体内模型解决了这个问题。在大鼠C6胶质瘤细胞中，瘦素预处理增强CCK激动剂（CCK-8 s）的Ca 2+动员。Janus激酶抑制剂（AG 490）或PI 3-激酶抑制剂（LY 294002）可降低这种瘦素作用。同时，单独的瘦素刺激未能动员Ca 2+，即使在过表达瘦素受体（C6-ObRb）的细胞。瘦素增加细胞核对磷酸化STAT 3（pSTAT 3）的免疫反应性，而CCK-8 s减少瘦素诱导的核pSTAT 3在这些细胞中的积累。在大鼠腹内侧下丘脑（VMH），瘦素诱导的动作电位放电增强，而核pSTAT 3与CCK-8 s的共刺激减少。为了进一步分析体内信号相互作用，CCK-1拮抗剂（lorglumide）腹腔注射大鼠1小时限制喂养。注射洛格鲁胺后3小时，食物获取增加。在这个时间点，核pSTAT 3增加，而c-Fos在VMH中减少。综上所述，这些结果表明，瘦素和CCK受体可能都有助于短期饱腹感，瘦素可以正向调节CCK信号。值得注意的是，在该实验范例中，核pSTAT 3水平与饱腹感水平负相关，这与通常描述的通过瘦素受体对长期饱腹感的转录调节相反。
Cholecystokinin (CCK) and leptin are satiety-controlling peptides, yet their interactive roles remain unclear. Here, we addressed this issue using in vitro and in vivo models. In rat C6 glioma cells, leptin pre-treatment enhanced Ca2+mobilization by a CCK agonist (CCK-8s). This leptin action was reduced by Janus kinase inhibitor (AG490) or PI3-kinase inhibitor (LY294002). Meanwhile, leptin stimulation alone failed to mobilize Ca2+even in cells overexpressing leptin receptors (C6-ObRb). Leptin increased nuclear immunoreactivity against phosphorylated STAT3 (pSTAT3) whereas CCK-8s reduced leptin-induced nuclear pSTAT3 accumulation in these cells. In the rat ventromedial hypothalamus (VMH), leptin-induced action potential firing was enhanced, whereas nuclear pSTAT3 was reduced by co-stimulation with CCK-8s. To further analyse in vivo signalling interplay, a CCK-1 antagonist (lorglumide) was intraperitoneally injected in rats following 1-h restricted feeding. Food access was increased 3-h after lorglumide injection. At this timepoint, nuclear pSTAT3 was increased whereas c-Fos was decreased in the VMH. Taken together, these results suggest that leptin and CCK receptors may both contribute to short-term satiety, and leptin could positively modulate CCK signalling. Notably, nuclear pSTAT3 levels in this experimental paradigm were negatively correlated with satiety levels, contrary to the generally described transcriptional regulation for long-term satiety via leptin receptors.