High-fat diet-induced brain region-specific phenotypic spectrum of CNS resident microglia.
High-fat diet-induced brain region-specific phenotypic spectrum of CNS resident microglia.
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DOI：
10.1007/s00401-016-1595-4
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发表时间：
2016-09
影响因子：
12.7
通讯作者：
Heppner FL
中科院分区：
文献类型：
--
作者：
Baufeld C;Osterloh A;Prokop S;Miller KR;Heppner FL
众所周知，高脂肪饮食(HFD)会在外周和中枢神经系统引起免疫反应。在外周脂肪组织中，这种免疫反应主要是由组织中招募的巨噬细胞介导的。同样，小胶质细胞是大脑的天然免疫细胞，已被证明发生在喂食高脂饮食的小鼠的下丘脑中。为了表征小胶质细胞对高脂肪饮食反应的性质，我们研究了高脂饮食3天和8周小鼠下丘脑小胶质细胞的表型谱，通过评估它们的组织反应和炎症特征。在HFD饲养8周后，我们观察到下丘脑中Iba1+髓系细胞和GFAP+星形胶质细胞的反应显著增加，但我们发现下丘脑髓系细胞的反应仅限于内源性小胶质细胞，而不是由浸润性髓系细胞介导。此外，肥胖的人被发现出现了下丘脑胶质细胞增多症的迹象，并加剧了小胶质细胞营养不良，这表明人类对饮食也有针对性的小胶质细胞反应。值得注意的是，发生在小鼠下丘脑的胶质反应并没有伴随促炎细胞因子的增加，而是伴随着抗炎反应。对分离的小胶质细胞的基因表达分析不仅证实了这一观察结果，还揭示了对微环境中的感知信号至关重要的小胶质细胞基因的下调。最后，我们证明了小胶质细胞在体内长期暴露于HFD不会损害细胞对额外刺激的反应能力，如脂多糖。综上所述，我们的发现支持这样的观点，即在啮齿动物和人类中，小胶质细胞对高脂肪饮食的反应是区域性的；然而，这种反应随着时间的推移而变化，因为它不仅是促炎的，接触HFD下丘脑的主要小胶质细胞也不是。本文的在线版本(doi：10.1007/s00401-0161595-4)包含补充材料，授权用户可以使用。
Diets high in fat (HFD) are known to cause an immune response in the periphery as well as the central nervous system. In peripheral adipose tissue, this immune response is primarily mediated by macrophages that are recruited to the tissue. Similarly, reactivity of microglia, the innate immune cells of the brain, has been shown to occur in the hypothalamus of mice fed a high-fat diet. To characterize the nature of the microglial response to diets high in fat in a temporal fashion, we studied the phenotypic spectrum of hypothalamic microglia of mice fed high-fat diet for 3 days and 8 weeks by assessing their tissue reaction and inflammatory signature. While we observed a significant increase in Iba1+ myeloid cells and a reaction of GFAP+ astrocytes in the hypothalamus after 8 weeks of HFD feeding, we found the hypothalamic myeloid cell reaction to be limited to endogenous microglia and not mediated by infiltrating myeloid cells. Moreover, obese humans were found to present with signs of hypothalamic gliosis and exacerbated microglia dystrophy, suggesting a targeted microglia response to diet in humans as well. Notably, the glial reaction occurring in the mouse hypothalamus was not accompanied by an increase in pro-inflammatory cytokines, but rather by an anti-inflammatory reaction. Gene expression analyses of isolated microglia not only confirmed this observation, but also revealed a downregulation of microglia genes important for sensing signals in the microenvironment. Finally, we demonstrate that long-term exposure of microglia to HFD in vivo does not impair the cell’s ability to respond to additional stimuli, like lipopolysaccharide. Taken together, our findings support the notion that microglia react to diets high in fat in a region-specific manner in rodents as well as in humans; however, this response changes over time as it is not exclusively pro-inflammatory nor does exposure to HFD prime microglia in the hypothalamus. The online version of this article (doi:10.1007/s00401-016-1595-4) contains supplementary material, which is available to authorized users.