Institute of Neuropathology, Charité, University Medicine Berlin, 10117, Berlin, Germany.
Freelance Bornavirus Workgroup, 14163, Berlin, Germany.
Brain Struct Funct. 2020 Jun;225(5):1459-1482. doi: 10.1007/s00429-020-02063-0. Epub 2020 May 11.
Human obesity epidemic is increasing worldwide with major adverse consequences on health. Among other possible causes, the hypothesis of an infectious contribution is worth it to be considered. Here, we report on an animal model of virus-induced obesity which might help to better understand underlying processes in human obesity. Eighty Wistar rats, between 30 and 60 days of age, were intracerebrally inoculated with Borna disease virus (BDV-1), a neurotropic negative-strand RNA virus infecting an unusually broad host spectrum including humans. Half of the rats developed fatal encephalitis, while the other half, after 3-4 months, continuously gained weight. At tripled weights, rats were sacrificed by trans-cardial fixative perfusion. Neuropathology revealed prevailing inflammatory infiltrates in the median eminence (ME), progressive degeneration of neurons of the paraventricular nucleus, the entorhinal cortex and the amygdala, and a strikingly high-grade involution of the hippocampus with hydrocephalus. Immune histology revealed that major BDV-1 antigens were preferentially present at glutamatergic receptor sites, while GABAergic areas remained free from BDV-1. Virus-induced suppression of the glutamatergic system caused GABAergic predominance. In the hypothalamus, this shifted the energy balance to the anabolic appetite-stimulating side governed by GABA, allowing for excessive fat accumulation in obese rats. Furthermore, inflammatory infiltrates in the ME and ventro-medial arcuate nucleus hindered free access of appetite-suppressing hormones leptin and insulin. The hormone transport system in hypothalamic areas outside the ME became blocked by excessively produced leptin, leading to leptin resistance. The resulting hyperleptinemic milieu combined with suppressed glutamatergic mechanisms was a characteristic feature of the found metabolic pathology. In conclusion, the study provided clear evidence that BDV-1 induced obesity in the rat model is the result of interdependent structural and functional metabolic changes. They can be explained by an immunologically induced hypothalamic microcirculation-defect, combined with a disturbance of neurotransmitter regulatory systems. The proposed mechanism may also have implications for human health. BDV-1 infection has been frequently found in depressive patients. Independently, comorbidity between depression and obesity has been reported, either. Future studies should address the exciting question of whether BDV-1 infection could be a link, whatsoever, between these two conditions.
人类肥胖症在全球范围内呈流行趋势，对健康造成了重大不利影响。在其他可能的原因中，感染的假设值得考虑。在这里，我们报告了一种病毒诱导肥胖的动物模型，这可能有助于更好地理解人类肥胖症的潜在过程。80 只 Wistar 大鼠，年龄在 30 到 60 天之间，被脑内接种博尔纳病病毒（BDV-1），这是一种神经嗜性负链 RNA 病毒，感染范围异常广泛，包括人类。一半的大鼠发展为致命性脑炎，而另一半大鼠在 3-4 个月后持续增重。当体重增加三倍时，大鼠通过心内固定液灌注处死。神经病理学显示，正中隆起（ME）中存在主要的炎症浸润，室旁核、内嗅皮层和杏仁核的神经元进行性退化，海马体呈现出显著的高级退行性变伴脑积水。免疫组织化学显示，BDV-1 的主要抗原优先存在于谷氨酸能受体部位，而 GABA 能区域则不受 BDV-1 的影响。病毒诱导的谷氨酸能系统抑制导致 GABA 能优势。在下丘脑，这种情况将能量平衡转移到由 GABA 控制的合成代谢食欲刺激侧，导致肥胖大鼠过度脂肪积累。此外，ME 和腹内侧弓状核中的炎症浸润阻碍了抑制食欲的激素瘦素和胰岛素的自由进入。ME 以外的下丘脑区域的激素转运系统被过度产生的瘦素阻断，导致瘦素抵抗。由此产生的高瘦素血症环境与抑制性谷氨酸能机制相结合，是所发现的代谢病理学的一个特征。总之，该研究提供了明确的证据，表明 BDV-1 在大鼠模型中诱导肥胖是结构和功能代谢变化相互依赖的结果。它们可以用免疫诱导的下丘脑微循环缺陷来解释，同时还伴有神经递质调节系统的紊乱。所提出的机制也可能与人类健康有关。BDV-1 感染在抑郁症患者中经常被发现。独立地，抑郁症和肥胖症之间的合并症也有报道。未来的研究应该解决一个令人兴奋的问题，即 BDV-1 感染是否可能是这两种情况之间的联系。
