Valdearcos Martin, Douglass John D, Robblee Megan M, Dorfman Mauricio D, Stifler Daniel R, Bennett Mariko L, Gerritse Irene, Fasnacht Rachael, Barres Ben A, Thaler Joshua P, Koliwad Suneil K
The Diabetes Center, University of California San Francisco, San Francisco, CA 94143, USA.
University of Washington Diabetes Institute, University of Washington, Seattle, WA 98109, USA; Department of Medicine, University of Washington, Seattle, WA 98109, USA.
Cell Metab. 2017 Jul 5;26(1):185-197.e3. doi: 10.1016/j.cmet.2017.05.015.
Dietary excess triggers accumulation of pro-inflammatory microglia in the mediobasal hypothalamus (MBH), but the components of this microgliosis and its metabolic consequences remain uncertain. Here, we show that microglial inflammatory signaling determines the immunologic response of the MBH to dietary excess and regulates hypothalamic control of energy homeostasis in mice. Either pharmacologically depleting microglia or selectively restraining microglial NF-κB-dependent signaling sharply reduced microgliosis, an effect that includes prevention of MBH entry by bone-marrow-derived myeloid cells, and greatly limited diet-induced hyperphagia and weight gain. Conversely, forcing microglial activation through cell-specific deletion of the negative NF-κB regulator A20 induced spontaneous MBH microgliosis and cellular infiltration, reduced energy expenditure, and increased both food intake and weight gain even in absence of a dietary challenge. Thus, microglial inflammatory activation, stimulated by dietary excess, orchestrates a multicellular hypothalamic response that mediates obesity susceptibility, providing a mechanistic rationale for non-neuronal approaches to treat metabolic diseases.
饮食过量会引发中基底下丘脑（MBH）中促炎性小胶质细胞的积累，但这种小胶质细胞增生的成分及其代谢后果仍不确定。在这里，我们表明小胶质细胞炎症信号决定了MBH对饮食过量的免疫反应，并调节小鼠下丘脑对能量稳态的控制。通过药物清除小胶质细胞或选择性抑制小胶质细胞中依赖NF-κB的信号传导，均可显著减少小胶质细胞增生，这一效应包括阻止骨髓来源的髓样细胞进入MBH，并极大地限制了饮食诱导的摄食过量和体重增加。相反，通过细胞特异性缺失负性NF-κB调节因子A20来强制小胶质细胞激活，会诱导MBH自发性小胶质细胞增生和细胞浸润，减少能量消耗，即使在没有饮食刺激的情况下也会增加食物摄入量和体重。因此，由饮食过量刺激引起的小胶质细胞炎症激活，协调了一种多细胞下丘脑反应，介导肥胖易感性，为治疗代谢性疾病的非神经元方法提供了机制依据。
