High-Fat Diet Induced Anxiety and Anhedonia: Impact on Brain Homeostasis and Inflammation
High-Fat Diet Induced Anxiety and Anhedonia: Impact on Brain Homeostasis and Inflammation
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DOI：
10.1038/npp.2015.357
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发表时间：
2016-06-01
影响因子：
7.6
通讯作者：
Duman, Ronald S.
中科院分区：
文献类型：
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作者：
Dutheil, Sophie;Ota, Kristie T.;Duman, Ronald S.
抑郁症和 2 型糖尿病 (T2D) 是高度共存的疾病，给公共卫生带来巨大负担。然而，人们对这些疾病背后的神经病理通路显然缺乏了解。本研究旨在阐明富含脂肪的饮食引起大脑多种并发症的分子机制，从而影响导致焦虑和抑郁行为的细胞内信号传导和基因表达。结果表明，高脂肪饮食（HFD；类似于 16 周）会导致焦虑和快感缺乏行为。重要的是，结果还表明，4 个月的 HFD 会破坏与突触可塑性和胰岛素信号/葡萄糖稳态有关的细胞内级联（即 Akt、细胞外信号调节激酶 (ERK)、P70S6K），以及皮质酮水平升高和先天免疫系统激活，包括炎性细胞因子（即 IL-6、IL-1 beta、TNF α）升高。有趣的是，速效抗抑郁药氯胺酮可以逆转 HFD 引起的行为缺陷，并激活前额皮质中的 ERK 和 P70S6 激酶信号传导。此外，我们发现通过重复给予嘌呤能P2X7受体抑制剂来药理阻断先天免疫炎性体系统，可以阻断HFD引起的焦虑。这些研究共同进一步阐明了慢性 HFD 暴露对焦虑和抑郁行为的影响，并为患有焦虑和抑郁的代谢性疾病或 T2D 患者确定了新的治疗靶点。
Depression and type 2 diabetes (T2D) are highly comorbid disorders that carry a large public health burden. However, there is a clear lack of knowledge of the neural pathological pathways underlying these illnesses. The present study aims to elucidate the molecular mechanisms by which a diet rich in fat can cause multiple complications in the brain, thereby affecting intracellular signaling and gene expression that underlie anxiety and depressive behaviors. The results show that a high-fat diet (HFD; similar to 16 weeks) causes anxiety and anhedonic behaviors. Importantly, the results also show that 4 months of HFD causes disruption of intracellular cascades involved in synaptic plasticity and insulin signaling/glucose homeostasis (ie, Akt, extracellular signal-regulated kinase (ERK), P70S6K), as well as increased corticosterone levels and activation of the innate immune system, including elevation of inflammatory cytokines (ie, IL-6, IL-1 beta, TNF alpha). Interestingly, the rapid acting antidepressant ketamine reverses the behavioral deficits caused by HFD and activates ERK and P70S6 kinase signaling in the prefrontal cortex. In addition, we found that pharmacological blockade of the innate immune inflammasome system by repeated administration of an inhibitor of the purinergic P2X7 receptor blocks the anxiety caused by HFD. Together these studies further elucidate the signaling pathways that underlie chronic HFD exposure on anxiety and depressive behaviors, and identify novel therapeutic targets for patients with metabolic disorder or T2D who suffer from anxiety and depression.