Cross down-regulation of leptin and insulin receptor expression and signalling in a human neuronal cell line
Cross down-regulation of leptin and insulin receptor expression and signalling in a human neuronal cell line
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DOI：
10.1042/bj20041621
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发表时间：
2005-06-15
影响因子：
4.1
通讯作者：
Taouis, M
中科院分区：
文献类型：
--
作者：
Benomar, Y;Roy, AF;Taouis, M
瘦素和胰岛素是下丘脑调节能量平衡和身体肥胖的主要信号。IR(胰岛素受体)和瘦素受体(长异构体，ObRb)共享许多信号级联，如JAK2/STAT-3(Janus kinase2/信号转导和转录激活因子3)和PI3K(磷脂酰肌醇3-激酶)；IR和ObRb之间的相互作用已在非神经细胞中描述。分化的人神经母细胞瘤(SH-SY5Y)细胞表达内源性OBR和IR，并通过刺激STAT-3和MAPK(丝裂原活化蛋白激酶)磷酸化和PI3K活性而对瘦素和胰岛素产生反应。胰岛素或瘦素处理SH-SY5Y细胞可增加基础STAT-3的磷酸化，但取消这些激素的急性效应，有趣的是，瘦素预处理消除了胰岛素效应，反之亦然。MAPK的磷酸化也得到了类似的结果，但瘦素或胰岛素预处理并不能完全消除胰岛素或瘦素的急性作用。我们还发现，胰岛素和瘦素分别通过IRS-1(胰岛素受体底物1)和IRS-2激活PI3K。此外，瘦素或胰岛素预处理增加基础PI3K活性和IRS-1或IRS-2与P85的相关性，并取消急性胰岛素或瘦素效应，同时下调IRS-1和IRS-2。最后，胰岛素预处理使瘦素结合量减少了约1/4。瘦素可使SH-SY5Y细胞胰岛素受体的表达减少40%，这很可能是瘦素和胰岛素受体交叉下调的原因。这些结果为瘦素和胰岛素受体在受体和下游信号水平的交叉下调提供了证据。这一发现可能有助于在神经元水平上理解瘦素抵抗和胰岛素抵抗之间的复杂关系。
Leptin and insulin are major signals to the hypothalamus to regulate energy homoeostasis and body adiposity. IR (insulin receptors) and leptin receptors (long isoform, ObRb) share a number of signalling cascades, such as JAK2/STAT-3 (Janus kinase 2/signal transduction and activator of transcription 3) and PI3K (phosphoinositide 3-kinase); the cross-talk between IR and ObRb have been described previously in non-neuronal cells. Differentiated human neuroblastoma (SH-SY5Y) cells express endogenous ObR and IR, and respond to leptin and insulin with stimulation of STAT-3 and MAPK (mitogen-activated protein kinase) phosphorylation, and PI3K activity. Insulin or leptin pre-treatment of SH-SY5Y cells increased basal STAT-3 phosphorylation, but abolished the acute effect of these hormones, and, interestingly, leptin pre-treatment abolished insulin effect and vice versa. Similar results were obtained for MAPK phosphorylation, but leptin or insulin pretreatment did not completely abolish the acute effect of insulin or leptin. We have also showed that insulin and leptin are able to activate PI3K through IRS-1 (insulin receptor substrate 1) and IRS-2 respectively. Furthermore, leptin or insulin pre-treatment increased basal PI3K activity and IRS-1 or IRS-2 association with p85 and abolished acute insulin or leptin effect, in addition to the down-regulation of IRS-1 and IRS-2. Finally, insulin pretreatment reduced leptin binding by approx. 60%, and leptin pre-treatment reduced the expression of insulin receptor by 40% in SH-SY5Y cells, which most likely accounts for the cross down-regulation of leptin and insulin receptors. These results provide evidence to suggest cross down-regulation of leptin and insulin receptors at both receptor and downstream signalling levels. This finding may contribute to the understanding of the complex relationship between leptin resistance and insulin resistance at the neuronal level.