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Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis

Abstract

All homeotherms use thermogenesis to maintain their core body temperature, ensuring that cellular functions and physiological processes can continue in cold environments1,2,3. In the prevailing model of thermogenesis, when the hypothalamus senses cold temperatures it triggers sympathetic discharge, resulting in the release of noradrenaline in brown adipose tissue and white adipose tissue4,5. Acting via the β3-adrenergic receptors, noradrenaline induces lipolysis in white adipocytes6, whereas it stimulates the expression of thermogenic genes, such as PPAR-γ coactivator 1a (Ppargc1a), uncoupling protein 1 (Ucp1) and acyl-CoA synthetase long-chain family member 1 (Acsl1), in brown adipocytes7,8,9. However, the precise nature of all the cell types involved in this efferent loop is not well established. Here we report in mice an unexpected requirement for the interleukin-4 (IL-4)-stimulated program of alternative macrophage activation in adaptive thermogenesis. Exposure to cold temperature rapidly promoted alternative activation of adipose tissue macrophages, which secrete catecholamines to induce thermogenic gene expression in brown adipose tissue and lipolysis in white adipose tissue. Absence of alternatively activated macrophages impaired metabolic adaptations to cold, whereas administration of IL-4 increased thermogenic gene expression, fatty acid mobilization and energy expenditure, all in a macrophage-dependent manner. Thus, we have discovered a role for alternatively activated macrophages in the orchestration of an important mammalian stress response, the response to cold.

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Figure 1: Exposure to cold environment induces alternative activation of adipose tissue macrophages.
Figure 2: Cold-induced metabolic adaptations require alternatively activated macrophages.
Figure 3: Alternatively activated macrophages produce catecholamines.
Figure 4: Alternative activation of macrophages increases energy expenditure.

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Acknowledgements

We thank members of the Chawla laboratory, A. Loh and C.-H. Lee for comments on the manuscript, and F. Kraemer for guidance on in vitro lipolysis assays. This work was supported by grants from the NIH (DK076760, HL076746, DK094641), Larry L. Hillblom Foundation Network Grant and an NIH Director’s Pioneer Award (DP1OD006415) to A.C. Support was provided by Stanford Graduate Fellowship (K.D.N.) and A-STAR Fellowship (Y.P.G). All animal care was in accordance with Stanford University’s A-PLAC and UCSF’s IACUC guidelines.

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K.D.N. and Y.Q. performed the experiments with assistance from X.C., J.M., T.D., Y.P.S.G. and L.M.; F.B., R.M.L. and A.C. were involved in project planning; K.D.N., Y.Q. and A.C. designed the experiments, analysed the data and wrote the manuscript.

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Correspondence to Ajay Chawla.

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The authors declare no competing financial interests.

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Nguyen, K., Qiu, Y., Cui, X. et al. Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis. Nature 480, 104–108 (2011). https://doi.org/10.1038/nature10653

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