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

Katrin Fischer, Henry H. Ruiz, Kevin Jhun, Brian Finan, Douglas J. Oberlin, Verena Van Der Heide, Anastasia V. Kalinovich, Natasa Petrovic, Yochai Wolf, Christoffer Clemmensen, Andrew C. Shin, Senad Divanovic, Frank Brombacher, Elke Glasmacher, Susanne Keipert, Martin Jastroch, Joachim Nagler, Karl Werner Schramm, Dasa Medrikova, Gustav ColldenStephen C. Woods, Stephan Herzig, Dirk Homann, Steffen Jung, Jan Nedergaard, Barbara Cannon, Matthias H. Tschöp, Timo D. Müller, Christoph Buettner

Research output: Contribution to journalArticlepeer-review

165 Scopus citations

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.

Original languageEnglish
Pages (from-to)623-630
Number of pages8
JournalNature Medicine
Volume23
Issue number5
DOIs
StatePublished - May 1 2017

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