UMR 9197Molecular Neuroendocrinology of Food Intake, University Paris-Sud, University Paris-Saclay, Orsay, France.
Department of Molecules and CircuitsCNRS UMR 9197, Molecular Neuroendocrinology of Food Intake, Paris-Saclay Institute of Neuroscience, Orsay, France.
J Endocrinol. 2018 Jul;238(1):77-89. doi: 10.1530/JOE-18-0096. Epub 2018 May 17.
Autophagy is a non-selective degradation pathway induced in energy-deprived cells and in non-starved cells by participating in cellular inflammatory responses mainly through the elimination of injured and aged mitochondria that constitute an important source of reactive oxygen species. We have previously reported that resistin/TLR4 signaling pathway induces inflammation and insulin resistance in neuronal cell. However, the impact of resistin-induced inflammation on neuronal autophagy is unknown. In the present study, we hypothesized that resistin-induced neuroinflammation could be attributed, at least partially, to the impairment of autophagy pathways in neuronal cells. Our data show that resistin decreases neuronal autophagy as evidenced by the repression of the main autophagy markers in SH-SY5Y human neuroblastoma cell line. Furthermore, the silencing of TLR4 completely abolished these effects. Resistin also inhibits AMPK phosphorylation and increases that of Akt/mTOR contrasting with activated autophagy where AMPK phosphorylation is augmented and mTOR inhibited. , resistin treatment inhibits the mRNA expression of autophagy markers in the hypothalamus of WT mice but not in -/- mice. In addition, resistin strongly diminished LC3 (a marker of autophagy) labeling in the arcuate nucleus of WT mice, and this effect is abolished in -/- mice. Taken together, our findings clearly reveal resistin/TLR4 as a new regulatory pathway of neuronal autophagy.
自噬是一种非选择性降解途径，在能量匮乏的细胞和非饥饿细胞中被诱导，主要通过消除构成活性氧重要来源的受损和衰老的线粒体来参与细胞炎症反应。我们之前曾报道过，抵抗素/TLR4 信号通路在神经元细胞中诱导炎症和胰岛素抵抗。然而，抵抗素诱导的炎症对神经元自噬的影响尚不清楚。在本研究中，我们假设抵抗素诱导的神经炎症至少部分归因于神经元细胞自噬途径的损伤。我们的数据表明，抵抗素通过抑制 SH-SY5Y 人神经母细胞瘤细胞系中的主要自噬标志物来降低神经元自噬。此外，TLR4 的沉默完全消除了这些作用。抵抗素还抑制 AMPK 磷酸化并增加 Akt/mTOR 的磷酸化，与激活的自噬相反，自噬中 AMPK 磷酸化增加，mTOR 受到抑制。此外，抵抗素处理抑制了 WT 小鼠下丘脑自噬标志物的 mRNA 表达，但在-/-小鼠中没有。此外，抵抗素强烈减少了 WT 小鼠弓状核中 LC3（自噬标志物）的标记，而在-/-小鼠中这种作用被消除。总之，我们的研究结果清楚地揭示了抵抗素/TLR4 是神经元自噬的一个新的调节途径。
