Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, the Netherlands.
Helmholtz Diabetes Center & German Center for Diabetes Research, Helmholtz Zentrum München & Division of Metabolic Diseases, Technische Universität München, Munich, Germany.
Cell Rep. 2017 Sep 26;20(13):3034-3042. doi: 10.1016/j.celrep.2017.09.008.
Consumption of a hypercaloric diet upregulates microglial innate immune reactivity along with a higher expression of lipoprotein lipase (Lpl) within the reactive microglia in the mouse brain. Here, we show that knockdown of the Lpl gene specifically in microglia resulted in deficient microglial uptake of lipid, mitochondrial fuel utilization shifting to glutamine, and significantly decreased immune reactivity. Mice with knockdown of the Lpl gene in microglia gained more body weight than control mice on a high-carbohydrate high-fat (HCHF) diet. In these mice, microglial reactivity was significantly decreased in the mediobasal hypothalamus, accompanied by downregulation of phagocytic capacity and increased mitochondrial dysmorphologies. Furthermore, HCHF-diet-induced POMC neuronal loss was accelerated. These results show that LPL-governed microglial immunometabolism is essential to maintain microglial function upon exposure to an HCHF diet. In a hypercaloric environment, lack of such an adaptive immunometabolic response has detrimental effects on CNS regulation of energy metabolism.
高热量饮食会使小胶质细胞的先天免疫反应上调，并且在反应性小胶质细胞中脂蛋白脂肪酶 (Lpl) 的表达更高。在这里，我们表明，特异性敲低小胶质细胞中的 Lpl 基因会导致小胶质细胞摄取脂质减少，线粒体燃料利用转向谷氨酰胺，并且免疫反应明显降低。在高脂肪高碳水化合物（HCHF）饮食中，敲低小胶质细胞中 Lpl 基因的小鼠比对照小鼠体重增加更多。在这些小鼠中，中脑下丘脑中的小胶质细胞反应性显著降低，伴随着吞噬能力下调和线粒体形态异常增加。此外，HCHF 饮食诱导的 POMC 神经元丢失加速。这些结果表明，LPL 调控的小胶质细胞免疫代谢对于在暴露于 HCHF 饮食时维持小胶质细胞功能至关重要。在高卡路里环境中，缺乏这种适应性免疫代谢反应会对中枢神经系统对能量代谢的调节产生不利影响。
