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

Abstract

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.

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Figure 1: Macrophage-restricted deletion of Mecp2 causes spontaneous obesity in adulthood.
Figure 2: Macrophage-restricted deletion of Mecp2 does not impair central function.
Figure 3: Macrophage-restricted deletion of Mecp2 impairs the steady-state function of BAT.
Figure 4: Normal acclimation to acute cold and hyperactivation of scWAT in the absence of Mecp2 in macrophages.
Figure 5: Effect of experimental denervation of BAT and diminished innervation of BAT in the absence of macrophage Mecp2.
Figure 6: Characterization of BAT macrophages.
Figure 7: Mecp2-mutant macrophages overexpress PlexinA4 and might interact with Sema6A-expressing sympathetic axons in iBAT.

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Acknowledgements

We thank the members of the Jung laboratory for discussion; R. Goldner for technical assistance; A. Rudich and M. Jastroch for advice and comments on the manuscript; G. Shakhar and R. Eilam for help with imaging and immunofluorescence; Z. Kam for writing an algorithm for the axon counting; and the Amit laboratory for advice on profiling. Supported by the Israeli Science Foundation (Jung laboratory), the European Research Council (340345 for the Jung laboratory), the University of Michigan–Israel Partnership for Research (Jung laboratory), the Lombroso fund (N.C.). the Perlman Family Foundation (Y.K.) and the Sarah and Rolando Uziel Research Associate Chair (Y.K.).

Author information

Authors and Affiliations

Authors

Contributions

Y.W., S.B.-H. and S.J. designed the study and wrote the manuscript; Y.W. and S.B.-H. performed most of the experimental work; N.C. performed neuron quantification; Z.H. established the RiboTag approach; H.S.S. and A.Y. provided reagents and critical advice for the neuronal analysis; Y.K., V.K. and A.B. provided help and advice with metabolic analysis, imaging analysis and mass spectrometry; E.D. provided bioinformatics analysis; and Y.S.-H. and L.C.-M. performed gene-expression profiling.

Corresponding author

Correspondence to Steffen Jung.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7 and Supplementary Tables 5 and 6 (PDF 2649 kb)

Supplementary Table 1

Genes enriched in BAT macrophages across macrophage population (XLSX 53 kb)

Supplementary Table 2

List of genes enriched in CX3CR1+ BAT macrophages (XLSX 50 kb)

Supplementary Table 3

List of genes enriched in CX3CR1- BAT macrophages (PDF 294 kb)

Supplementary Table 4

Part a: genes upregulated in MeCP2 null macrophages (PDF 114 kb)

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Wolf, Y., Boura-Halfon, S., Cortese, N. et al. Brown-adipose-tissue macrophages control tissue innervation and homeostatic energy expenditure. Nat Immunol 18, 665–674 (2017). https://doi.org/10.1038/ni.3746

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