Physiological Laboratory, School of Biomedical Sciences, University of Liverpool, Liverpool, UK.
Endocrinology. 2010 Aug;151(8):3589-99. doi: 10.1210/en.2010-0106. Epub 2010 Jun 9.
Food intake is regulated by signals from peripheral organs, but the way these are integrated remains uncertain. Cholecystokinin (CCK) from the intestine and leptin from adipocytes interact to inhibit food intake. Our aim was to examine the hypothesis that these interactions occur at the level of vagal afferent neurons via control of the immediate early gene EGR1. We now report that CCK stimulates redistribution to the nucleus of early growth response factor-1 (EGR1) in these neurons in vivo and in culture, and these effects are not dependent on EGR1 synthesis. Leptin stimulates EGR1 expression; leptin alone does not stimulate nuclear translocation, but it strongly potentiates the action of CCK. Ghrelin inhibits CCK-stimulated nuclear translocation of EGR1 and leptin-stimulated EGR1 expression. Expression of the gene encoding the satiety peptide cocaine- and amphetamine-regulated transcript (CARTp) is stimulated by CCK via an EGR1-dependent mechanism, and this is strongly potentiated by leptin. Leptin potentiated inhibition of food intake by endogenous CCK in the rat in conditions reflecting changes in EGR1 activation. The data indicate that by separately regulating EGR1 activation and synthesis, CCK and leptin interact cooperatively to define the capacity for satiety signaling by vagal afferent neurons; manipulation of these interactions may be therapeutically beneficial.
食物摄入受来自外周器官的信号调节，但这些信号如何整合仍不确定。肠源性胆囊收缩素 (CCK) 和脂肪细胞源性瘦素相互作用以抑制食物摄入。我们的目的是检验这样一种假设，即这些相互作用通过迷走传入神经元中即刻早期基因 EGR1 的控制而发生。我们现在报告 CCK 刺激这些神经元体内和体外的早期生长反应因子-1（EGR1）重新分布到核内，并且这些作用不依赖于 EGR1 的合成。瘦素刺激 EGR1 的表达；瘦素本身不能刺激核易位，但它强烈增强 CCK 的作用。胃饥饿素抑制 CCK 刺激的 EGR1 核易位和瘦素刺激的 EGR1 表达。通过 EGR1 依赖的机制，CCK 刺激饱腹感肽可卡因和安非他命调节转录物（CARTp）基因的表达，并且瘦素强烈增强这种作用。在反映 EGR1 激活变化的条件下，瘦素增强了内源性 CCK 对大鼠摄食的抑制作用。这些数据表明，CCK 和瘦素通过分别调节 EGR1 的激活和合成，相互合作以确定迷走传入神经元饱腹感信号的能力；对这些相互作用的操纵可能具有治疗益处。
