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Nat Med. 2017 May;23(5):623-630. doi: 10.1038/nm.4316. Epub 2017 Apr 17.

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

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Institute for Diabetes and Obesity, Helmholtz Diabetes Center (HDC) at Helmholtz Zentrum München and German Center for Diabetes Research (DZD), 85764 München-Neuherberg, Germany.
Division of Metabolic Diseases, Department of Medicine, Technische Universität München, 80333 Munich, Germany.
Diabetes, Metabolism and Obesity Institute, Icahn School of Medicine at Mount Sinai, NY 10029, USA.
Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 10691 Stockholm, Sweden.
Weizmann Institute of Science Department of Immunology, 76100 Rehovot, Israel.
Department of Pediatrics, Division of Immunobiology, Cincinnati Children's Hospital Medical Center, OH 45229 Cincinnati, USA.
International Center for Genetic Engineering and Biotechnology, Cape Town component & University of Cape Town, IDM, Division Immunology & SAMRC, South Africa.
Department of Animal Physiology, Faculty of Biology, Philipps University of Marburg, 35032 Marburg, Germany.
Molecular Exposomics, Helmholtz Zentrum München, German National Diabetes Center (DZD), 85764 Neuherberg, Germany.
Institute for Diabetes and Cancer (IDC), Helmholtz Zentrum München, German National Diabetes Center (DZD), 85764 Neuherberg, Germany, and Joint IDC-Heidelberg Translational Diabetes Program, Inner Medicine I, Heidelberg University Hospital, 69120 Heidelberg, Germany.
Metabolic Diseases Institute, Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, OH 45237 Cincinnati, USA.
Department of Medicine, Icahn School of Medicine at Mount Sinai, NY 10029, USA.
Contributed equally


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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