Activation of the omega-3 fatty acid receptor GPR120 mediates anti-inflammatory actions in immortalized hypothalamic neurons.
Activation of the omega-3 fatty acid receptor GPR120 mediates anti-inflammatory actions in immortalized hypothalamic neurons.
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DOI：
10.1186/1742-2094-11-60
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发表时间：
2014-03-27
影响因子：
9.3
通讯作者：
Belsham DD
中科院分区：
文献类型：
--
作者：
Wellhauser L;Belsham DD
营养过剩和随之而来的下丘脑炎症是代谢性疾病（如肥胖症和糖尿病）发展的一个主要永久因素。CNS的发炎神经元不能适当地调节能量稳态，导致葡萄糖处理、进食和体重的致病性变化。下丘脑神经元对局部和外周来源的促炎信号特别敏感，并且正是这些神经元在高脂肪喂养时首先发炎。鉴于代谢疾病的流行，正在努力确定这种炎症状态的治疗靶点。至少在外周，ω-3脂肪酸及其受体G蛋白偶联受体120（GPR 120）已成为公认的靶点。GPR 120在下丘脑或CNS中的作用一般知之甚少。在这里，我们介绍了一种新的，永生化的细胞模型，来自大鼠下丘脑，rHypoE-7，研究GPR 120激活在单个神经元的水平。在存在或不存在多不饱和ω-3脂肪酸二十二碳六烯酸（DHA）的情况下，通过定量逆转录酶-PCR（qRT-PCR）研究了暴露于肿瘤坏死因子α（TNFα）处理后促炎细胞因子的基因表达水平。信号转导通路参与也进行了研究，使用磷酸特异性抗体的关键蛋白质的蛋白质印迹分析。重要的是，rHypoE-7细胞在暴露于TNFα后表现出转录和翻译炎症反应，并表达丰富水平的GPR 120，其在功能上对DHA有反应。DHA预处理可预防炎症状态，这种作用可通过降低内源性GPR 120水平来抑制。GPR 120可激活AKT（蛋白激酶B）和ERK（细胞外信号调节激酶）;然而，这种omega-3脂肪酸（FA）受体的抗炎作用不依赖于AKT和ERK，可能涉及GPR 120-转化生长因子-β-激活的激酶1结合蛋白（TAB 1）相互作用，如在外周中鉴定的。总之，GPR 120在下丘脑神经元系rHypoE-7中具有功能活性，其中它介导DHA的抗炎作用以减少对TNFα的炎症反应。
Overnutrition and the ensuing hypothalamic inflammation is a major perpetuating factor in the development of metabolic diseases, such as obesity and diabetes. Inflamed neurons of the CNS fail to properly regulate energy homeostasis leading to pathogenic changes in glucose handling, feeding, and body weight. Hypothalamic neurons are particularly sensitive to pro-inflammatory signals derived locally and peripherally, and it is these neurons that become inflamed first upon high fat feeding. Given the prevalence of metabolic disease, efforts are underway to identify therapeutic targets for this inflammatory state. At least in the periphery, omega-3 fatty acids and their receptor, G-protein coupled receptor 120 (GPR120), have emerged as putative targets. The role for GPR120 in the hypothalamus or CNS in general is poorly understood. Here we introduce a novel, immortalized cell model derived from the rat hypothalamus, rHypoE-7, to study GPR120 activation at the level of the individual neuron. Gene expression levels of pro-inflammatory cytokines were studied by quantitative reverse transcriptase-PCR (qRT-PCR) upon exposure to tumor necrosis factor α (TNFα) treatment in the presence or absence of the polyunsaturated omega-3 fatty acid docosahexaenoic acid (DHA). Signal transduction pathway involvement was also studied using phospho-specific antibodies to key proteins by western blot analysis. Importantly, rHypoE-7 cells exhibit a transcriptional and translational inflammatory response upon exposure to TNFα and express abundant levels of GPR120, which is functionally responsive to DHA. DHA pretreatment prevents the inflammatory state and this effect was inhibited by the reduction of endogenous GPR120 levels. GPR120 activates both AKT (protein kinase b) and ERK (extracellular signal-regulated kinase); however, the anti-inflammatory action of this omega-3 fatty acid (FA) receptor is AKT- and ERK-independent and likely involves the GPR120-transforming growth factor-β-activated kinase 1 binding protein (TAB1) interaction as identified in the periphery. Taken together, GPR120 is functionally active in the hypothalamic neuronal line, rHypoE-7, wherein it mediates the anti-inflammatory actions of DHA to reduce the inflammatory response to TNFα.
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影响因子：
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