Brown-adipose-tissue macrophages control tissue innervation and homeostatic energy expenditure

Nat Immunol. 2017 Jun;18(6):665-674. doi: 10.1038/ni.3746. Epub 2017 May 1.


Tissue macrophages provide immunological defense and contribute to the establishment and maintenance of tissue homeostasis. Here we used constitutive and inducible mutagenesis to delete the nuclear transcription regulator Mecp2 in macrophages. Mice that lacked the gene encoding Mecp2, which is associated with Rett syndrome, in macrophages did not show signs of neurodevelopmental disorder but displayed spontaneous obesity, which was linked to impaired function of brown adipose tissue (BAT). Specifically, mutagenesis of a BAT-resident Cx3Cr1+ macrophage subpopulation compromised homeostatic thermogenesis but not acute, cold-induced thermogenesis. Mechanistically, malfunction of BAT in pre-obese mice with mutant macrophages was associated with diminished sympathetic innervation and local titers of norepinephrine, which resulted in lower expression of thermogenic factors by adipocytes. Mutant macrophages overexpressed the signaling receptor and ligand PlexinA4, which might contribute to the phenotype by repulsion of sympathetic axons expressing the transmembrane semaphorin Sema6A. Collectively, we report a previously unappreciated homeostatic role for macrophages in the control of tissue innervation. Disruption of this circuit in BAT resulted in metabolic imbalance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes, Brown
  • Adipose Tissue, Brown / immunology*
  • Adipose Tissue, Brown / innervation
  • Adipose Tissue, Brown / metabolism
  • Animals
  • Axons / metabolism
  • CX3C Chemokine Receptor 1
  • Energy Metabolism / immunology
  • Flow Cytometry
  • Homeostasis
  • Immunoblotting
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Methyl-CpG-Binding Protein 2 / genetics*
  • Mice
  • Mutagenesis, Site-Directed
  • Nerve Tissue Proteins / metabolism
  • Norepinephrine / metabolism
  • Obesity / genetics
  • Real-Time Polymerase Chain Reaction
  • Receptors, Cell Surface / metabolism
  • Receptors, Chemokine / metabolism
  • Semaphorins / metabolism
  • Sympathetic Nervous System / metabolism*
  • Thermogenesis / immunology*


  • CX3C Chemokine Receptor 1
  • Cx3cr1 protein, mouse
  • Mecp2 protein, mouse
  • Methyl-CpG-Binding Protein 2
  • Nerve Tissue Proteins
  • Plxna4 protein, mouse
  • Receptors, Cell Surface
  • Receptors, Chemokine
  • Sema6a protein, mouse
  • Semaphorins
  • Norepinephrine