Brief exposure to obesogenic diet disrupts brain dopamine networks
Brief exposure to obesogenic diet disrupts brain dopamine networks
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DOI：
10.1371/journal.pone.0191299
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发表时间：
2018-04-26
期刊：
影响因子：
3.7
通讯作者：
Avison, Malcolm J.
中科院分区：
文献类型：
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作者：
Barry, Robert L.;Byun, Nellie E.;Avison, Malcolm J.
目的我们之前已经证明，通过下游信号激酶 Akt 的胰岛素信号传导是多巴胺转运蛋白 (DAT) 活性的有效调节剂，可微调突触处的多巴胺 (DA) 信号传导。这表明神经元胰岛素受体信号传导受损（饮食引起的肥胖的一个标志）可能导致 DA 传输受损。我们测试了短期（两周）致肥胖的高脂肪 (HF) 饮食是否会降低纹状体 Akt 活性（中枢胰岛素的标志物）、受体信号传导以及钝化纹状体和多巴胺能网络对安非他明 (AMPH) 的反应。方法我们使用 AMPH 作为功能性磁共振成像 (fMRI) 测定中的探针，检查了两周 HF 饮食对大鼠纹状体 DAT 活性的影响，并绘制了对纹状体 DAT 活性的影响。使用相关性和排列分析，AMPH 诱发关键多巴胺能目标与其投影区域之间的功能连接。我们使用纹状体提取物中 Akt 底物 GSK3 α 的磷酸化作为胰岛素受体信号传导的测量。最后，我们使用 [F-18]fallypride 正电子发射断层扫描 (PET) 证实了 HF 饮食对纹状体 DA D2 受体 (D2R) 可用性的影响。结果我们发现仅喂食 HF 饮食两周的大鼠纹状体 Akt 活性降低，这是纹状体胰岛素受体信号减弱和纹状体对 AMPH 反应减弱的标志。高频喂养还减少了与享乐喂养有关的中脑边缘（伏隔核-前扣带回）和感觉运动回路（尾状核/壳核-丘脑-感觉运动皮层）元素之间的相互作用。 HF 喂养的动物中 D2R 的可用性降低。结论这些研究支持这样的假设：短期 HF 喂养后中枢胰岛素信号传导和多巴胺能神经传递已经发生改变。由于 AMPH 在很大程度上通过 DAT 诱导 DA 流出和大脑激活，因此这些研究结果表明，通过 HF 饮食减弱的中枢神经系统胰岛素受体信号传导可能会损害 DA 稳态，从而扰乱参与享乐喂养调节的认知和奖励回路。
ObjectiveWe have previously demonstrated that insulin signaling, through the downstream signaling kinase Akt, is a potent modulator of dopamine transporter (DAT) activity, which fine-tunes dopamine (DA) signaling at the synapse. This suggests a mechanism by which impaired neuronal insulin receptor signaling, a hallmark of diet-induced obesity, may contribute to impaired DA transmission. We tested whether a short-term (two-week) obesogenic high-fat (HF) diet could reduce striatal Akt activity, a marker of central insulin, receptor signaling and blunt striatal and dopaminergic network responsiveness to amphetamine (AMPH).MethodsWe examined the effects of a two-week HF diet on striatal DAT activity in rats, using AMPH as a probe in a functional magnetic resonance imaging (fMRI) assay, and mapped the disruption in AMPH-evoked functional connectivity between key dopaminergic targets and their projection areas using correlation and permutation analyses. We used phosphorylation of the Akt substrate GSK3 alpha in striatal extracts as a measure of insulin receptor signaling. Finally, we confirmed the impact of HF diet on striatal DA D2 receptor (D2R) availability using [F-18] fallypride positron emission tomography (PET).ResultsWe found that rats fed a HF diet for only two weeks have reductions in striatal Akt activity, a marker of decreased striatal insulin receptor signaling and blunted striatal responsiveness to AMPH. HF feeding also reduced interactions between elements of the mesolimbic (nucleus accumbens-anterior cingulate) and sensorimotor circuits (caudate/putamen-thalamus-sensorimotor cortex) implicated in hedonic feeding. D2R availability was reduced in HF-fed animals.ConclusionThese studies support the hypothesis that central insulin signaling and dopaminergic neuro-transmission are already altered after short-term HF feeding. Because AMPH induces DA efflux and brain activation, in large part via DAT, these findings suggest that blunted central nervous system insulin receptor signaling through a HF diet can impair DA homeostasis, thereby disrupting cognitive and reward circuitry involved in the regulation of hedonic feeding.