TY - JOUR

T1 - Alternatively activated macrophages do not synthesize catecholamines or contribute to adipose tissue adaptive thermogenesis

AU - Fischer, Katrin

AU - Ruiz, Henry H

AU - Jhun, Kevin

AU - Finan, Brian

AU - Oberlin, Douglas J

AU - van der Heide, Verena

AU - Kalinovich, Anastasia V

AU - Petrovic, Natasa

AU - Wolf, Yochai

AU - Clemmensen, Christoffer

AU - Shin, Andrew C

AU - Divanovic, Senad

AU - Brombacher, Frank

AU - Glasmacher, Elke

AU - Keipert, Susanne

AU - Jastroch, Martin

AU - Nagler, Joachim

AU - Schramm, Karl-Werner

AU - Medrikova, Dasa

AU - Collden, Gustav

AU - Woods, Stephen C

AU - Herzig, Stephan

AU - Homann, Dirk

AU - Jung, Steffen

AU - Nedergaard, Jan

AU - Cannon, Barbara

AU - Tschöp, Matthias H

AU - Müller, Timo D

AU - Buettner, Christoph

PY - 2017/5

Y1 - 2017/5

N2 - 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.

AB - 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.

KW - Adaptation, Physiological

KW - Adipocytes

KW - Adipose Tissue

KW - Adipose Tissue, Brown

KW - Adipose Tissue, White

KW - Animals

KW - Blotting, Western

KW - Body Composition

KW - Catecholamines

KW - Cell Differentiation

KW - Culture Media, Conditioned

KW - Energy Metabolism

KW - Flow Cytometry

KW - Fluorescent Antibody Technique

KW - Gene Expression Profiling

KW - Interleukin-4

KW - Macrophages

KW - Mice

KW - Mice, Knockout

KW - Norepinephrine

KW - Receptors, Adrenergic, beta-3

KW - Receptors, Cell Surface

KW - Thermogenesis

KW - Tyrosine 3-Monooxygenase

KW - Uncoupling Protein 1

KW - Journal Article

U2 - 10.1038/nm.4316

DO - 10.1038/nm.4316

M3 - Journal article

C2 - 28414329

VL - 23

SP - 623

EP - 630

JO - Nature Medicine

JF - Nature Medicine

SN - 1078-8956

IS - 5

ER -