Sex differences in microglial CX3CR1 signalling determine obesity susceptibility in mice

Mauricio D. Dorfman, Jordan E. Krull, John D. Douglass, Rachael Fasnacht, Fernando Lara-Lince, Thomas H. Meek, Xiaogang Shi, Vincent Damian, Hong T. Nguyen, Miles E. Matsen, Gregory J. Morton and Joshua P. Thaler ()
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Mauricio D. Dorfman: University of Washington
Jordan E. Krull: University of Washington
John D. Douglass: University of Washington
Rachael Fasnacht: University of Washington
Fernando Lara-Lince: University of Washington
Thomas H. Meek: University of Washington
Xiaogang Shi: University of Washington
Vincent Damian: University of Washington
Hong T. Nguyen: University of Washington
Miles E. Matsen: University of Washington
Gregory J. Morton: University of Washington
Joshua P. Thaler: University of Washington

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/ncomms14556

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