Metabolic syndrome' in the brain: deficiency in omega-3 fatty acid exacerbates dysfunctions in insulin receptor signalling and cognition
Metabolic syndrome' in the brain: deficiency in omega-3 fatty acid exacerbates dysfunctions in insulin receptor signalling and cognition
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DOI：
10.1113/jphysiol.2012.230078
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发表时间：
2012-05-01
影响因子：
5.5
通讯作者：
Gomez-Pinilla, Fernando
中科院分区：
文献类型：
--
作者：
Agrawal, Rahul;Gomez-Pinilla, Fernando
我们进行了研究，以确定代谢综合征（MetS）对大脑的影响，以及通过饮食干预调节这些影响的可能性。此外，我们还评估了脑代谢紊乱影响突触可塑性和认知的潜在机制。我们报告高果糖饮食消耗导致胰岛素抵抗指数，胰岛素和甘油三酯水平的增加，这是代谢的特征。喂食缺乏n-3的老鼠在巴恩斯迷宫中表现出记忆缺陷，果糖的摄入进一步加剧了这种缺陷。反过来，缺乏n-3的饮食和果糖干预会破坏海马中的胰岛素受体信号，胰岛素受体及其下游效应物Akt的磷酸化水平下降就是证据。我们发现，在缺乏n-3的饮食中摄入高果糖会破坏膜内平衡，这可以通过n-6/n-3脂肪酸比例和4-羟基壬烯醛（脂质过氧化的标志）水平的增加来证明。由于n-3缺乏和果糖处理导致的脑能代谢紊乱，AMPK磷酸化及其上游调节剂LKB1的显著降低以及Sir2水平的降低证明了这一点。n-3缺乏和果糖导致CREB、synapsin I和synaptophysin磷酸化水平降低，表明代谢功能障碍对突触可塑性的影响。饮食中n-3脂肪酸的存在改善了与果糖处理相关的代谢功能障碍的所有参数。结果表明，饮食中n-3脂肪酸缺乏通过调节胰岛素受体信号传导和突触可塑性，提高代谢功能障碍和认知功能受损的易感性。
We pursued studies to determine the effects of the metabolic syndrome (MetS) on brain, and the possibility of modulating these effects by dietary interventions. In addition, we have assessed potential mechanisms by which brain metabolic disorders can impact synaptic plasticity and cognition. We report that high-dietary fructose consumption leads to an increase in insulin resistance index, and insulin and triglyceride levels, which characterize MetS. Rats fed on an n-3 deficient diet showed memory deficits in a Barnes maze, which were further exacerbated by fructose intake. In turn, an n-3 deficient diet and fructose interventions disrupted insulin receptor signalling in hippocampus as evidenced by a decrease in phosphorylation of the insulin receptor and its downstream effector Akt. We found that high fructose consumption with an n-3 deficient diet disrupts membrane homeostasis as evidenced by an increase in the ratio of n-6/n-3 fatty acids and levels of 4-hydroxynonenal, a marker of lipid peroxidation. Disturbances in brain energy metabolism due to n-3 deficiency and fructose treatments were evidenced by a significant decrease in AMPK phosphorylation and its upstream modulator LKB1 as well as a decrease in Sir2 levels. The decrease in phosphorylation of CREB, synapsin I and synaptophysin levels by n-3 deficiency and fructose shows the impact of metabolic dysfunction on synaptic plasticity. All parameters of metabolic dysfunction related to the fructose treatment were ameliorated by the presence of dietary n-3 fatty acid. Results showed that dietary n-3 fatty acid deficiency elevates the vulnerability to metabolic dysfunction and impaired cognitive functions by modulating insulin receptor signalling and synaptic plasticity.