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Alternatively activated macrophages do not synthesize catecholamines or contribute to adipose tissue adaptive thermogenesis

Abstract

Adaptive thermogenesis is the process of heat generation in response to cold stimulation. It is under the control of the sympathetic nervous system, whose chief effector is the catecholamine norepinephrine (NE). NE enhances thermogenesis through β3-adrenergic receptors to activate brown adipose tissue and by 'browning' white adipose tissue. Recent studies have reported that alternative activation of macrophages in response to interleukin (IL)-4 stimulation induces the expression of tyrosine hydroxylase (TH), a key enzyme in the catecholamine synthesis pathway, and that this activation provides an alternative source of locally produced catecholamines during the thermogenic process. Here we report that the deletion of Th in hematopoietic cells of adult mice neither alters energy expenditure upon cold exposure nor reduces browning in inguinal adipose tissue. Bone marrow–derived macrophages did not release NE in response to stimulation with IL-4, and conditioned media from IL-4-stimulated macrophages failed to induce expression of thermogenic genes, such as uncoupling protein 1 (Ucp1), in adipocytes cultured with the conditioned media. Furthermore, chronic treatment with IL-4 failed to increase energy expenditure in wild-type, Ucp1−/− and interleukin-4 receptor-α double-negative (Il4ra−/−) mice. In agreement with these findings, adipose-tissue-resident macrophages did not express TH. Thus, we conclude that alternatively activated macrophages do not synthesize relevant amounts of catecholamines, and hence, are not likely to have a direct role in adipocyte metabolism or adaptive thermogenesis.

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Figure 1: Selective deletion of Th in peripheral but not CNS tissues results in peripheral catecholamine depletion and impaired thermoregulation.
Figure 2: Energy expenditure of WT and THΔper chimera.
Figure 3: Effect of alternatively activated macrophages from BALB/c mice on thermogenesis in primary inguinal white and brown adipocytes.
Figure 4: Effect of IL-4 on energy expenditure and thermogenesis in WT and Il4ra−/− mice at different temperatures.
Figure 5: Effect of IL-4 on thermogenesis in WT and Ucp1/– mice.
Figure 6: TH staining of BAT macrophages.

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Acknowledgements

We thank A. Fedl, L. Sehrer, L. Müller, S. Jall, D. Heine, T. Stankiewicz, K. Gaul and A. Stanley for assistance with in vitro and ex vivo analysis. The mice with floxed Th were kindly provided by R. Palmiter. This work was supported in part by funding to M.H.T. from the Alexander von Humboldt Foundation, the Helmholtz Alliance ICEMED & the Helmholtz Initiative on Personalized Medicine iMed by Helmholtz Association, and the Helmholtz cross-program topic “Metabolic Dysfunction.” This work was further supported by grants from the German Research Foundation DFG-TS226/1-1, DFG-TS226/3-1, SFB1123, Nutripathos Project ANR-15-CE14-0030, European Research Council ERC AdG HypoFlam no. 695054 (to M.H.T.); DFG He3260/8-1, the EU FP7 Network “DIABAT,” the EU ITN Network “TRAIN” 721531 (to S.H.); NIH R01 AA023416, DK082724 and a career-development award from the American Diabetes Association (to C.B.); NIH R01DK099222 (to S.D.); NIH DK17844 (to S.C.W.); the Israeli Science Foundation and European Research Council (AdvERC grant 340345) (to S.J.) and the Swedish Research Council and the Knut and Alice Wallenberg Foundation (to J.N. and B.C.). We would like to dedicate this manuscript to the memory of Tim Bartness, whose work delineates the important role of the SNS in adipose tissue function.

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K.F. co-conceptualized the project, designed and performed in vitro, in vivo and ex vivo experiments, analyzed and interpreted data and wrote the manuscript. B.F. and C.C. helped to design experiments and interpreted data. H.H.R., K.J., D.J.O., V.v.d.H., A.C.S. and D.H. performed, analyzed and interpreted the inducible THΔper mouse, validation of antibodies and BM chimera data. A.V.K. and N.P. performed, analyzed and interpreted in vivo experiments in Ucp1−/− mice. J.N. and K.-W.S. performed, analyzed and interpreted catecholamine data. Y.W. and S.J. performed, analyzed and interpreted tyrosine hydroxylase staining. F.B. generated the Il4ra−/− mouse. S.D., E.G., S.K., M.J., D.M., G.C., S.H., J.N. and B.C. helped to design experiments and interpreted data. S.C.W. helped with the interpretation of data and drafting the manuscript. M.H.T. co-conceptualized the project and interpreted all data. T.D.M. and C.B. co-conceptualized the project, interpreted all data, supervised the studies and wrote the manuscript.

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Correspondence to Timo D Müller or Christoph Buettner.

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The authors declare no competing financial interests.

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Supplementary Figures 1–12 and Supplementary Table 1 (PDF 21691 kb)

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Fischer, K., Ruiz, H., Jhun, K. et al. Alternatively activated macrophages do not synthesize catecholamines or contribute to adipose tissue adaptive thermogenesis. Nat Med 23, 623–630 (2017). https://doi.org/10.1038/nm.4316

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