TLR4 inhibitor TAK-242 attenuates the adverse neural effects of diet-induced obesity.
TLR4 inhibitor TAK-242 attenuates the adverse neural effects of diet-induced obesity.
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DOI：
10.1186/s12974-018-1340-0
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发表时间：
2018-11-05
影响因子：
9.3
通讯作者：
Pike CJ
中科院分区：
文献类型：
--
作者：
Moser VA;Uchoa MF;Pike CJ
肥胖对大脑健康产生负面影响，包括神经发生减少，学习和记忆受损，患阿尔茨海默病和相关痴呆症的风险增加。由于肥胖促进神经胶质细胞活化、慢性神经炎症和神经损伤，因此小胶质细胞与肥胖的有害作用有关。在介导外周组织中肥胖影响方面特别重要的一种途径是Toll样受体4（TLR 4）信号传导。TLR 4通路在介导肥胖的不良神经结果中的潜在贡献尚未得到很好的解决。为了研究这种可能性，我们研究了药物抑制TLR 4如何影响饮食诱导的肥胖的外周和神经结果。在存在或不存在特异性TLR 4信号传导抑制剂TAK-242的情况下，雄性C57 BL 6/J小鼠维持对照或高脂肪饮食12周。检查的结果包括代谢指标、一系列行为评估、小胶质细胞活化、全身和神经炎症以及神经健康终点。在外周，TAK-242给药与脂肪组织炎症的部分抑制相关，但对体重、肥胖和一系列代谢指标无显著影响。在脑中，接受TAK-242给药的肥胖小鼠表现出小胶质细胞活化显著减少、神经发生水平提高和阿尔茨海默病相关淀粉样蛋白生成途径抑制。高脂饮食和TAK-242仅对一系列行为指标产生非常轻微的影响。这些结果表明TLR 4抑制对肥胖的神经后果具有显著的保护作用，这些发现进一步定义了小胶质细胞在肥胖介导的结果中的作用，并确定了改善肥胖个体大脑健康的策略。本文的在线版本（10.1186/s12974-018-1340-0）包含补充材料，可供授权用户使用。
Obesity exerts negative effects on brain health, including decreased neurogenesis, impaired learning and memory, and increased risk for Alzheimer’s disease and related dementias. Because obesity promotes glial activation, chronic neuroinflammation, and neural injury, microglia are implicated in the deleterious effects of obesity. One pathway that is particularly important in mediating the effects of obesity in peripheral tissues is toll-like receptor 4 (TLR4) signaling. The potential contribution of TLR4 pathways in mediating adverse neural outcomes of obesity has not been well addressed. To investigate this possibility, we examined how pharmacological inhibition of TLR4 affects the peripheral and neural outcomes of diet-induced obesity. Male C57BL6/J mice were maintained on either a control or high-fat diet for 12 weeks in the presence or absence of the specific TLR4 signaling inhibitor TAK-242. Outcomes examined included metabolic indices, a range of behavioral assessments, microglial activation, systemic and neuroinflammation, and neural health endpoints. Peripherally, TAK-242 treatment was associated with partial inhibition of inflammation in the adipose tissue but exerted no significant effects on body weight, adiposity, and a range of metabolic measures. In the brain, obese mice treated with TAK-242 exhibited a significant reduction in microglial activation, improved levels of neurogenesis, and inhibition of Alzheimer-related amyloidogenic pathways. High-fat diet and TAK-242 were associated with only very modest effects on a range of behavioral measures. These results demonstrate a significant protective effect of TLR4 inhibition on neural consequences of obesity, findings that further define the role of microglia in obesity-mediated outcomes and identify a strategy for improving brain health in obese individuals. The online version of this article (10.1186/s12974-018-1340-0) contains supplementary material, which is available to authorized users.
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影响因子：
3.7
作者：
Barron AM;Rosario ER;Elteriefi R;Pike CJ
通讯作者：
Pike CJ
影响因子：
9.3
作者：
Cherry JD;Olschowka JA;O'Banion MK
通讯作者：
O'Banion MK
影响因子：
9.3
作者：
De Luca SN;Ziko I;Sominsky L;Nguyen JC;Dinan T;Miller AA;Jenkins TA;Spencer SJ
通讯作者：
Spencer SJ
影响因子：
9.9
作者：
Cournot, M.;Marquie, J. -C.;Ruidavets, J. -B.
通讯作者：
Ruidavets, J. -B.
影响因子：
3.3
作者：
BO, L;MORK, S;TRAPP, BD
通讯作者：
TRAPP, BD