Palmitoylethanolamide dampens neuroinflammation and anxiety-like behavior in obese mice.
Palmitoylethanolamide dampens neuroinflammation and anxiety-like behavior in obese mice.
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DOI：
10.1016/j.bbi.2022.02.008
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发表时间：
2022-05
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影响因子：
--
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高脂饮食（HFD）消费导致肥胖和慢性低度炎症状态，称为炎症后反应。值得注意的是，由于循环游离脂肪酸和细胞因子水平的增加，后炎症有助于神经炎症。这表明在肥胖相关的情绪障碍的发病机制中，外周和中枢对应物之间存在严格的相互作用。在这种情况下，内部下丘脑回路的损伤与与情绪处理相关的其他大脑区域的改变（即，海马和杏仁核）。棕榈酰乙醇胺（PEA）是N-酰基乙醇胺家族的一种内源性脂质介质，因其在中枢和外周水平的多效性而被广泛研究。我们的研究旨在阐明PEA限制HFD喂养的肥胖小鼠实验模型中肥胖诱导的焦虑样行为和神经炎症相关特征的能力。PEA治疗促进肥胖小鼠的焦虑样行为和全身炎症的改善，降低血清促炎介质（即，TNF-α、IL-1β、MCP-1、LPS）。在杏仁核中，PEA增加了多巴胺的周转，以及GABA水平。PEA还可对抗HPA轴的过度激活，降低下丘脑促肾上腺皮质激素释放激素及其1型受体的表达。此外，PEA减弱了Iba-1和GFAP的免疫反应性，并减少了下丘脑和海马中的促炎通路和细胞因子的产生。这一发现以及海马中肥大细胞标志物（糜酶1和类胰蛋白酶β2）的转录减少，表明PEA神经保护作用背后的免疫细胞活化减弱。肥胖驱动的神经炎症也与海马中血脑屏障（BBB）的破坏有关。PEA限制了白蛋白外渗，并恢复了HFD修饰的紧密连接转录。为了获得机制的见解，我们设计了一个体外模型的代谢损伤使用人神经母细胞瘤SH-SY 5 Y细胞侮辱的混合葡萄糖胺和葡萄糖。在这里，PEA以PPAR-α依赖性方式直接抵消炎症和线粒体功能障碍，因为受体的药理学阻断恢复了其作用。我们的研究结果加强了PEA在肥胖相关的神经精神共病，控制神经炎症，BBB破坏和神经递质失衡参与行为功能障碍的治疗潜力。
High-fat diet (HFD) consumption leads to obesity and a chronic state of low-grade inflammation, named metainflammation. Notably, metainflammation contributes to neuroinflammation due to the increased levels of circulating free fatty acids and cytokines. It indicates a strict interplay between peripheral and central counterparts in the pathogenic mechanisms of obesity-related mood disorders. In this context, the impairment of internal hypothalamic circuitry runs in tandem with the alteration of other brain areas associated with emotional processing (i.e., hippocampus and amygdala). Palmitoylethanolamide (PEA), an endogenous lipid mediator belonging to the N-acylethanolamines family, has been extensively studied for its pleiotropic effects both at central and peripheral level. Our study aimed to elucidate PEA capability in limiting obesity-induced anxiety-like behavior and neuroinflammation-related features in an experimental model of HFD-fed obese mice. PEA treatment promoted an improvement in anxiety-like behavior of obese mice and the systemic inflammation, reducing serum pro-inflammatory mediators (i.e., TNF-α, IL-1β, MCP-1, LPS). In the amygdala, PEA increased dopamine turnover, as well as GABA levels. PEA also counteracted the overactivation of HPA axis, reducing the expression of hypothalamic corticotropin-releasing hormone and its type 1 receptor. Moreover, PEA attenuated the immunoreactivity of Iba-1 and GFAP and reduced pro-inflammatory pathways and cytokine production in both the hypothalamus and hippocampus. This finding, together with the reduced transcription of mast cell markers (chymase 1 and tryptase β2) in the hippocampus, indicated the weakening of immune cell activation underlying the neuroprotective effect of PEA. Obesity-driven neuroinflammation was also associated with the disruption of blood–brain barrier (BBB) in the hippocampus. PEA limited the albumin extravasation and restored tight junction transcription modified by HFD. To gain mechanistic insight, we designed an in vitro model of metabolic injury using human neuroblastoma SH-SY5Y cells insulted by a mix of glucosamine and glucose. Here, PEA directly counteracted inflammation and mitochondrial dysfunction in a PPAR-α-dependent manner since the pharmacological blockade of the receptor reverted its effects. Our results strengthen the therapeutic potential of PEA in obesity-related neuropsychiatric comorbidities, controlling neuroinflammation, BBB disruption, and neurotransmitter imbalance involved in behavioral dysfunctions.
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影响因子：
15.1
作者：
Cristiano, Claudia;Pirozzi, Claudio;Raso, Giuseppina Mattace
通讯作者：
Raso, Giuseppina Mattace
影响因子：
5
作者：
Li, Yitian;Zhou, Pan;Li, Yuhang
通讯作者：
Li, Yuhang
DOI：
10.1016/j.trsl.2017.10.004
发表时间：
2018-01
期刊：
Translational research : the journal of laboratory and clinical medicine
影响因子：
--
作者：
Li C;Xu MM;Wang K;Adler AJ;Vella AT;Zhou B
通讯作者：
Zhou B
影响因子：
10.6
作者：
Locci, Andrea;Pinna, Graziano
通讯作者：
Pinna, Graziano
影响因子：
2.5
作者：
Buckman, Laura B.;Thompson, Misty M.;Moreno, Heidi N.;Ellacott, Kate L. J.
通讯作者：
Ellacott, Kate L. J.