Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, Division of Metabolic Diseases, Department of Medicine, Technische Universität München, German Center for Diabetes Research (DZD), 85764 München-Neuherberg, Germany.
Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, 1105AZ Amsterdam, The Netherlands.
Nat Commun. 2017 May 10;8:15143. doi: 10.1038/ncomms15143.
Consuming a calorically dense diet stimulates microglial reactivity in the mediobasal hypothalamus (MBH) in association with decreased number of appetite-curbing pro-opiomelanocortin (POMC) neurons; whether the reduction in POMC neuronal function is secondary to the microglial activation is unclear. Here we show that in hypercaloric diet-induced obese mice, persistently activated microglia in the MBH hypersecrete TNFα that in turn stimulate mitochondrial ATP production in POMC neurons, promoting mitochondrial fusion in their neurites, and increasing POMC neuronal firing rates and excitability. Specific disruption of the gene expressions of TNFα downstream signals TNFSF11A or NDUFAB1 in the MBH of diet-induced obese mice reverses mitochondrial elongation and reduces obesity. These data imply that in a hypercaloric environment, persistent elevation of microglial reactivity and consequent TNFα secretion induces mitochondrial stress in POMC neurons that contributes to the development of obesity.
摄入高热量的饮食会刺激中脑腹侧被盖区（MBH）的小胶质细胞反应，伴随着食欲抑制型 pro-opiomelanocortin（POMC）神经元数量减少；POMC 神经元功能的减少是否是小胶质细胞激活的继发事件尚不清楚。在这里，我们表明，在高热量饮食诱导的肥胖小鼠中，MBH 中持续激活的小胶质细胞过度分泌 TNFα，反过来刺激 POMC 神经元中线粒体 ATP 的产生，促进其神经突中的线粒体融合，并增加 POMC 神经元的放电频率和兴奋性。在饮食诱导肥胖的小鼠的 MBH 中特异性破坏 TNFα 下游信号 TNFSF11A 或 NDUFAB1 的基因表达可逆转线粒体伸长并减少肥胖。这些数据表明，在高卡路里环境中，小胶质细胞反应的持续升高和随之而来的 TNFα 分泌会导致 POMC 神经元的线粒体应激，从而导致肥胖的发生。
