A rapid microglial metabolic response controls metabolism and improves memory.
A rapid microglial metabolic response controls metabolism and improves memory.
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快速的小胶质细胞代谢反应控制新陈代谢并提高记忆力。
DOI：
10.1101/2023.04.03.535373
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Henderson
中科院分区：
文献类型：
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作者：
Drougard,Anne;Ma,EricH;Wegert,Vanessa;Sheldon,Ryan;Panzeri,Ilaria;Vatsa,Naman;Apostle,Stefanos;Fagnocchi,Luca;Schaf,Judith;Gossens,Klaus;Völker,Josephine;Pang,Shengru;Bremser,Anna;Dror,Erez;Giacona,Francesca;Sagar;Henderson
长期高脂饮食会引发代谢功能障碍，包括肥胖、胰岛素抵抗和糖尿病。高脂肪摄入是如何首先触发这些病理生理状态的，目前尚不清楚。在这里，我们确定了一种急性小胶质细胞代谢反应，它能迅速将高脂饮食(HFD)的摄入转化为对新陈代谢和空间/学习记忆的意外有益影响。高脂肪摄入会迅速增加脑脊液中棕榈酸酯的水平，并引发以线粒体膜激活和分裂为特征的小胶质细胞代谢活化浪潮，以及代谢向有氧糖酵解的倾斜。这些影响可以在整个大脑中检测到，并且可以在暴露于HFD的短短12小时内检测到。在体内，小胶质细胞消融和条件性DRp1缺失表明，小胶质细胞代谢反应是HFD急性效应所必需的。13C示踪实验表明，除了通过β氧化处理外，小胶质细胞还将相当一部分棕榈酸酯分流到细胞外环境中，以乳酸、谷氨酸、琥珀酸的形式重新释放生物能碳，有趣的是，神经保护代谢物衣康酸。总而言之，这些数据确定小胶质细胞是大脑中一个关键的营养调节节点，它能代谢掉有害的脂肪酸，并释放出相同的碳，作为周围细胞的替代生物能量和保护性底物。这些数据表明，短期服用HFD对学习和记忆有令人惊讶的有益影响。
Chronic high-fat feeding triggers metabolic dysfunction including obesity, insulin resistance, and diabetes. How high-fat intake first triggers these pathophysiological states remains unknown. Here, we identify an acute microglial metabolic response that rapidly translates intake of high-fat diet (HFD) to a surprisingly beneficial effect on metabolism and spatial/learning memory. High-fat intake rapidly increases palmitate levels in cerebrospinal fluid and triggers a wave of microglial metabolic activation characterized by mitochondrial membrane activation and fission as well as metabolic skewing toward aerobic glycolysis. These effects are detectable throughout the brain and can be detected within as little as 12 hr of HFD exposure. In vivo, microglial ablation and conditional DRP1 deletion show that the microglial metabolic response is necessary for the acute effects of HFD. 13 C-tracing experiments reveal that in addition to processing via β-oxidation, microglia shunt a substantial fraction of palmitate toward anaplerosis and re-release of bioenergetic carbons into the extracellular milieu in the form of lactate, glutamate, succinate, and intriguingly, the neuroprotective metabolite itaconate. Together, these data identify microglia as a critical nutrient regulatory node in the brain, metabolizing away harmful fatty acids and liberating the same carbons as alternate bioenergetic and protective substrates for surrounding cells. The data identify a surprisingly beneficial effect of short-term HFD on learning and memory.
苏云金芽孢杆菌的分析化学
DOI：
--
发表时间：
1990
期刊：
影响因子：
--
作者：
L. Hickle;W. Fitch
通讯作者：
W. Fitch