Sex differences in microglial CX3CR1 signalling determine obesity susceptibility in mice.
Sex differences in microglial CX3CR1 signalling determine obesity susceptibility in mice.
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DOI：
10.1038/ncomms14556
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发表时间：
2017-02-22
影响因子：
16.6
通讯作者：
Thaler JP
中科院分区：
文献类型：
--
作者：
Dorfman MD;Krull JE;Douglass JD;Fasnacht R;Lara-Lince F;Meek TH;Shi X;Damian V;Nguyen HT;Matsen ME;Morton GJ;Thaler JP
雌性小鼠比雄性小鼠更不容易受到高脂肪饮食喂养的负面代谢后果的影响，原因尚不完全清楚。在这里，我们通过CX3CL1-CX3CR1通路识别下丘脑小胶质细胞激活的性别差异，该通路介导雌性小鼠对饮食诱导的肥胖的抵抗力。喂食高脂饮食的雌性小鼠保持CX3CL1-CX3CR1水平，而雄性小鼠则表现出配体和受体表达的减少。雌性CX3CR1基因敲除小鼠出现了类似雄性的下丘脑小胶质细胞积聚和激活，并伴随着它们对饮食诱导的肥胖的敏感度显著增加。相反，通过中枢药物给药或病毒介导的下丘脑过度表达增加雄性小鼠脑内CX3CL1的水平，会将它们转化为类似雌性的代谢表型，从而减少小胶质细胞的激活和体重增加。这些数据表明，小胶质细胞激活在调节能量平衡方面存在性别差异，并确认CX3CR1信号是治疗肥胖症的潜在治疗靶点。与雄性不同，雌性小鼠在喂食高脂肪食物时，对下丘脑炎症和体重增加具有抵抗力。在这里，作者揭示了通过CX3CR1信号对下丘脑小胶质细胞激活的性别特异性调节，为饮食诱导肥胖的不同易感性提供了潜在的机制。
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. Unlike males, female mice are resistant to hypothalamic inflammation and weight gain when fed a high-fat diet. Here, the authors reveal sex-specific regulation of hypothalamic microglial activation through CX3CR1 signalling, providing a potential mechanism for differential susceptibility to diet-induced obesity.