Vanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
Department of Radiology and Radiological Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
PLoS One. 2018 Apr 26;13(4):e0191299. doi: 10.1371/journal.pone.0191299. eCollection 2018.
We 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).
We 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 GSK3α 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 [18F]fallypride positron emission tomography (PET).
We 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.
These studies support the hypothesis that central insulin signaling and dopaminergic neurotransmission 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.
我们之前已经证明，胰岛素信号通过下游信号激酶 Akt，是调节多巴胺转运体（DAT）活性的有力调节剂，从而精细调节突触处的多巴胺（DA）信号。这表明一种机制，即饮食诱导肥胖中受损的神经元胰岛素受体信号可能导致 DA 传递受损。我们测试了短期（两周）致肥胖高脂肪（HF）饮食是否会降低纹状体 Akt 活性，这是中枢胰岛素受体信号的标志物，并减弱纹状体和多巴胺能网络对安非他命（AMPH）的反应。
我们使用 AMPH 作为功能磁共振成像（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，并使用相关和置换分析绘制了关键多巴胺能靶点与其投射区域之间 AMPH 诱发功能连接的中断图。我们使用纹状体提取物中 Akt 底物 GSK3α 的磷酸化作为胰岛素受体信号的度量。最后，我们使用 [18F]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。
我们发现，仅接受 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降低和纹状体对 AMPH 反应迟钝的标志物。HF 喂养还降低了参与享乐性喂养的中边缘（伏隔核-前扣带皮层）和感觉运动回路（尾状核/壳核-丘脑-感觉运动皮层）之间的相互作用。HF 喂养的动物中 D2R 可用性降低。
这些研究支持了以下假设，即短期 HF 喂养后中枢胰岛素信号和多巴胺能神经传递已经改变。由于 AMPH 诱导 DA 外排和大脑激活，在很大程度上是通过 DAT 诱导的，这些发现表明，通过 HF 饮食减弱中枢神经系统胰岛素受体信号会破坏 DA 稳态，从而破坏参与调节享乐性喂养的认知和奖励回路。
