Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Clinical Medicine and Surgery, University of Naples "Federico II", Naples 80131, Italy.
Cell Metab. 2019 Nov 5;30(5):952-962.e5. doi: 10.1016/j.cmet.2019.08.010. Epub 2019 Sep 5.
Microglia play a crucial role in immune responses, including inflammation. Diet-induced obesity (DIO) triggers microglia activation and hypothalamic inflammation as early as 3 days after high-fat diet (HFD) exposure, before changes in body weight occur. The intracellular mechanism(s) responsible for HFD-induced microglia activation is ill defined. Here, we show that in vivo, HFD induced a rapid and transient increase in uncoupling protein 2 (Ucp2) mRNA expression together with changes in mitochondrial dynamics. Selective microglial deletion of Ucp2 prevented changes in mitochondrial dynamics and function, microglia activation, and hypothalamic inflammation. In association with these, male and female mice were protected from HFD-induced obesity, showing decreased feeding and increased energy expenditure that were associated with changes in the synaptic input organization and activation of the anorexigenic hypothalamic POMC neurons and astrogliosis. Together, our data point to a fuel-availability-driven mitochondrial mechanism as a major player of microglia activation in the central regulation of DIO.
小胶质细胞在免疫反应中发挥着关键作用，包括炎症反应。饮食诱导的肥胖（DIO）在高脂肪饮食（HFD）暴露后仅 3 天就会引发小胶质细胞激活和下丘脑炎症，而此时体重尚未发生变化。负责 HFD 诱导小胶质细胞激活的细胞内机制尚不清楚。在这里，我们表明，在体内，HFD 诱导解偶联蛋白 2（Ucp2）mRNA 表达的快速和短暂增加，同时伴随着线粒体动力学的变化。Ucp2 的选择性小胶质细胞缺失可防止线粒体动力学和功能、小胶质细胞激活以及下丘脑炎症的改变。与此相关的是，雄性和雌性小鼠免受 HFD 诱导的肥胖的影响，表现出摄食量减少和能量消耗增加，这与突触输入组织的变化以及厌食性下丘脑 POMC 神经元和星形胶质细胞的激活有关。总之，我们的数据表明，作为 DIO 中中枢调节中小胶质细胞激活的主要参与者，燃料可用性驱动的线粒体机制是一个关键因素。
