Sex differences in microglial CX3CR1 signalling determine obesity susceptibility in mice

作者：Mauricio D. Dorfman, Jordan Edward Krull, John D. Douglass, Rachael D. Fasnacht, Fernando Lara-Lince, Thomas H. Meek, Xiaogang Shi, Vincent M. Damian, Nguyễn Thị Hồng, Miles E. Matsen, Gregory J. Morton, Joshua P. Thaler · 发表于：Nature Communications · 年份：2017 · DOI：10.1038/ncomms14556 · 被引用次数：175 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Chemokine receptors and signaling、Adipokines, Inflammation, and Metabolic Diseases

Female mice are less susceptible to the negative metabolic consequences of high-fat diet feeding than male mice, for reasons that are incompletely understood. Here we identify sex-specific differences in hypothalamic microglial activation via the CX3CL1-CX3CR1 pathway that mediate the resistance of female mice to diet-induced obesity. Female mice fed a high-fat diet maintain CX3CL1-CX3CR1 levels while male mice show reductions in both ligand and receptor expression. Female Cx3cr1 knockout mice develop 'male-like' hypothalamic microglial accumulation and activation, accompanied by a marked increase in their susceptibility to diet-induced obesity. Conversely, increasing brain CX3CL1 levels in male mice through central pharmacological administration or virally mediated hypothalamic overexpression converts them to a 'female-like' metabolic phenotype with reduced microglial activation and body-weight gain. These data implicate sex differences in microglial activation in the modulation of energy homeostasis and identify CX3CR1 signalling as a potential therapeutic target for the treatment of obesity.