Cui Hong, Cai Fang, Belsham Denise D
Department of Physiology, University of Toronto, Toronto, ON, Canada M5S 1A8.
FASEB J. 2006 Dec;20(14):2654-6. doi: 10.1096/fj.06-5989fje. Epub 2006 Oct 31.
The adipokine leptin signals energy status to the hypothalamus, which triggers a network of neuropeptide responses. Each hypothalamic cell type expresses a unique complement of neuropeptides, receptors, and second messengers; thus each likely responds specifically to peripheral hormones. We describe here the analysis of leptin signaling in a clonal population of mouse neurotensin (NT) -expressing hypothalamic neurons, N-39. Leptin induced phosphorylation of STAT3 and MAPK ERK1/2, but not the downstream effector of PI3K, Akt, and also induced c-Fos protein. We found activation of p38 MAPK by leptin, accompanied by phosphorylation of its downstream effector ATF-1. Phosphorylation of ATF-1 is blocked by the p38 MAPK inhibitor SB 203580. We linked this signaling directly to NT transcription. Protein binding analysis indicates that both ATF-1 and c-Fos are capable of binding to the mouse NT/N gene predominantly at physiological or high concentrations of leptin. The evidence indicates activation of distinct leptin signal transduction pathways that directly result in changes in NT gene expression and links these specific neurons to the control of energy homeostasis.
脂肪因子瘦素向下丘脑传递能量状态信号，进而触发一系列神经肽反应。下丘脑的每种细胞类型都表达独特的神经肽、受体和第二信使组合；因此，每种细胞可能对外周激素有特异性反应。我们在此描述了对表达小鼠神经降压素（NT）的下丘脑神经元克隆群体N-39中瘦素信号传导的分析。瘦素诱导STAT3和MAPK ERK1/2磷酸化，但不诱导PI3K的下游效应器Akt磷酸化，同时还诱导c-Fos蛋白表达。我们发现瘦素激活了p38 MAPK，并伴随其下游效应器ATF-1的磷酸化。ATF-1的磷酸化被p38 MAPK抑制剂SB 203580阻断。我们将此信号传导直接与NT转录联系起来。蛋白质结合分析表明，在生理浓度或高浓度瘦素条件下，ATF-1和c-Fos都能够与小鼠NT/N基因结合。证据表明，不同的瘦素信号转导途径被激活，直接导致NT基因表达发生变化，并将这些特定神经元与能量稳态控制联系起来。
