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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Cannon, B. & Nedergaard, J. Brown adipose tissue: function and physiological significance. Physiol. Rev. 84, 277–359 (2004)
Lowell, B. B. & Spiegelman, B. M. Towards a molecular understanding of adaptive thermogenesis. Nature 404, 652–660 (2000)
Tseng, Y. H., Cypess, A. M. & Kahn, C. R. Cellular bioenergetics as a target for obesity therapy. Nature Rev. Drug Discov. 9, 465–482 (2010)
Nakamura, K. & Morrison, S. F. A thermosensory pathway that controls body temperature. Nature Neurosci. 11, 62–71 (2008)
Morrison, S. F., Nakamura, K. & Madden, C. J. Central control of thermogenesis in mammals. Exp. Physiol. 93, 773–797 (2008)
Nedergaard, J., Bengtsson, T. & Cannon, B. New powers of brown fat: fighting the metabolic syndrome. Cell Metab. 13, 238–240 (2011)
Ellis, J. M. et al. Adipose acyl-CoA synthetase-1 directs fatty acids toward β-oxidation and is required for cold thermogenesis. Cell Metab. 12, 53–64 (2010)
Enerbäck, S. et al. Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature 387, 90–94 (1997)
Puigserver, P. et al. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92, 829–839 (1998)
Cannon, B. & Nedergaard, J. Nonshivering thermogenesis and its adequate measurement in metabolic studies. J. Exp. Biol. 214, 242–253 (2011)
Gordon, S. Alternative activation of macrophages. Nature Rev. Immunol. 3, 23–35 (2003)
Odegaard, J. I. & Chawla, A. Alternative macrophage activation and metabolism. Annu. Rev. Pathol. 6, 275–297 (2011)
Martinez, F. O., Helming, L. & Gordon, S. Alternative activation of macrophages: an immunologic functional perspective. Annu. Rev. Immunol. 27, 451–483 (2009)
Herbert, D. R. et al. Alternative macrophage activation is essential for survival during schistosomiasis and downmodulates T helper 1 responses and immunopathology. Immunity 20, 623–635 (2004)
Watt, M. J. et al. Reduced plasma FFA availability increases net triacylglycerol degradation, but not GPAT or HSL activity, in human skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 287, E120–E127 (2004)
Haemmerle, G. et al. Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase. Science 312, 734–737 (2006)
Lass, A. et al. Adipose triglyceride lipase-mediated lipolysis of cellular fat stores is activated by CGI-58 and defective in Chanarin-Dorfman Syndrome. Cell Metab. 3, 309–319 (2006)
Flierl, M. A. et al. Phagocyte-derived catecholamines enhance acute inflammatory injury. Nature 449, 721–725 (2007)
Brown, S. W. et al. Catecholamines in a macrophage cell line. J. Neuroimmunol. 135, 47–55 (2003)
Zhou, Q. Y., Quaife, C. J. & Palmiter, R. D. Targeted disruption of the tyrosine hydroxylase gene reveals that catecholamines are required for mouse fetal development. Nature 374, 640–643 (1995)
Yoshida, T., Sakane, N., Wakabayashi, Y., Umekawa, T. & Kondo, M. Anti-obesity and anti-diabetic effects of CL 316,243, a highly specific β3-adrenoceptor agonist, in yellow KK mice. Life Sci. 54, 491–498 (1994)
Kosteli, A. et al. Weight loss and lipolysis promote a dynamic immune response in murine adipose tissue. J. Clin. Invest. 120, 3466–3479 (2010)
Odegaard, J. I. et al. Alternative M2 activation of Kupffer cells by PPARδa ameliorates obesity-induced insulin resistance. Cell Metab. 7, 496–507 (2008)
Odegaard, J. I. et al. Macrophage-specific PPARγ controls alternative activation and improves insulin resistance. Nature 447, 1116–1120 (2007)
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.
Author information
Authors and Affiliations
Contributions
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.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Information
This file contains Supplementary Tables 1-3 and Supplementary Figures 1-15 with legends. (PDF 5635 kb)
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nature10653
This article is cited by
-
M2 macrophages independently promote beige adipogenesis via blocking adipocyte Ets1
Nature Communications (2024)
-
Telmisartan and candesartan promote browning of white adipose tissue and reverse fatty liver changes in high fat diet fed male albino rats
Naunyn-Schmiedeberg's Archives of Pharmacology (2024)
-
Unraveling the complex roles of macrophages in obese adipose tissue: an overview
Frontiers of Medicine (2024)
-
Prospects of potential adipokines as therapeutic agents in obesity-linked atherogenic dyslipidemia and insulin resistance
The Egyptian Heart Journal (2023)
-
Physiology and diseases of tissue-resident macrophages
Nature (2023)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.