SRA

Tissue resident macrophages provide a systemic innate immune defense network and critically contribute to establishment and maintenance of tissue homeostasis. Here we used constitutive and inducible mutagenesis to delete the nuclear transcription regulator methyl-CpG binding protein 2 (MeCP2) in defined tissue macrophages. Animals lacking the Rett syndrome-associated gene in macrophages did not show signs of neurodevelopmental disorder, but surprisingly displayed altered body composition and spontaneous obesity. This phenotype involved neither hyper-phagia, primary hyper-insulinemia nor inflammation, but rather could be linked to impaired brown adipose tissue (BAT) function. Specifically, mutagenesis of a BAT-resident CX3CR1+ macrophage subpopulation compromised homeostatic, though not acute cold-induced thermogenesis. Mechanistically, steady state BAT malfunction of pre-obese mice harboring mutant macrophages was associated with decreased sympathetic innervation and lower local norepinephrine titers, resulting in reduced adipocyte expression of the thermogenic factors UCP1 and DIO2. Mutant macrophages were found to over-express PlexinA4, which might contribute to the phenotype by repulsion of Sema6A-expressing sympathetic axons. Collectively, we report a previously unappreciated homeostatic role of macrophages in the control of tissue innervation, disruption of which in BAT results in metabolic imbalance. Overall design: BAT macrophages taken from CX3CR1-cre, CX3CR1-CreER:tomato and CX3CR1-CreER:mecp2:ribo-tag for gene profiling in steady state