title: Sex differences in microglial CX3CR1 signalling determine obesity susceptibility in mice.
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.
authors.affiliation: UW Diabetes Institute and Department of Medicine, University of Washington, Seattle, Washington 98109, USA.
authors.forename: Mauricio D
authors.initials: MD
authors.lastname: Dorfman
authors.affiliation: UW Diabetes Institute and Department of Medicine, University of Washington, Seattle, Washington 98109, USA.
authors.forename: Jordan E
authors.initials: JE
authors.lastname: Krull
authors.affiliation: UW Diabetes Institute and Department of Medicine, University of Washington, Seattle, Washington 98109, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Douglass
authors.affiliation: UW Diabetes Institute and Department of Medicine, University of Washington, Seattle, Washington 98109, USA.
authors.forename: Rachael
authors.initials: R
authors.lastname: Fasnacht
authors.affiliation: UW Diabetes Institute and Department of Medicine, University of Washington, Seattle, Washington 98109, USA.
authors.forename: Fernando
authors.initials: F
authors.lastname: Lara-Lince
authors.affiliation: UW Diabetes Institute and Department of Medicine, University of Washington, Seattle, Washington 98109, USA.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Meek
authors.affiliation: UW Diabetes Institute and Department of Medicine, University of Washington, Seattle, Washington 98109, USA.
authors.forename: Xiaogang
authors.initials: X
authors.lastname: Shi
authors.affiliation: UW Diabetes Institute and Department of Medicine, University of Washington, Seattle, Washington 98109, USA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Damian
authors.affiliation: UW Diabetes Institute and Department of Medicine, University of Washington, Seattle, Washington 98109, USA.
authors.forename: Hong T
authors.initials: HT
authors.lastname: Nguyen
authors.affiliation: UW Diabetes Institute and Department of Medicine, University of Washington, Seattle, Washington 98109, USA.
authors.forename: Miles E
authors.initials: ME
authors.lastname: Matsen
authors.affiliation: UW Diabetes Institute and Department of Medicine, University of Washington, Seattle, Washington 98109, USA.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Morton
authors.affiliation: UW Diabetes Institute and Department of Medicine, University of Washington, Seattle, Washington 98109, USA.
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Thaler
mesh_terms: D000818:Animals; D000073883:CX3C Chemokine Receptor 1 / Q000172:deficiency / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D059305:Diet, High-Fat; D004198:Disease Susceptibility; D004967:Estrogens / Q000494:pharmacology; D005247:Feeding Behavior / Q000187:drug effects; D005260:Female; D007031:Hypothalamus / Q000473:pathology; D007249:Inflammation / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D009765:Obesity / Q000378:metabolism* / Q000473:pathology*; D010641:Phenotype; D012727:Sex Characteristics; D015398:Signal Transduction; D015430:Weight Gain
chemical_list: C491049:Aif1 protein, mouse; D000073883:CX3C Chemokine Receptor 1; D002135:Calcium-Binding Proteins; C471885:Cx3cr1 protein, mouse; D004967:Estrogens; D008840:Microfilament Proteins