title: Macrophage infiltration into obese adipose tissues suppresses the induction of UCP1 level in mice.
abstract: Emergence of thermogenic adipocytes such as brown and beige adipocytes is critical for whole body energy metabolism. Promoting the emergence of these adipocytes, which increase energy expenditure, could be a viable strategy in treating obesity and its related diseases. However, little is known regarding the mechanisms that regulate the emergence of these adipocytes in obese adipose tissue. Here, we demonstrated that classically activated macrophages (M1 Mϕ) suppress the induction of thermogenic adipocytes in obese adipose tissues of mice. Cold exposure significantly induced the expression levels of uncoupling protein-1 (UCP1), which is a mitochondrial protein unique in thermogenic adipocytes, in C57BL/6 mice fed a normal diet. However, UCP1 induction was significantly suppressed in adipose tissues of C57BL/6 mice fed a high-fat diet, into which M1 Mϕ infiltrated. Depletion of M1 Mϕ using clodronate liposomes eliminated the suppressive effect and markedly reduced the mRNA level of tumor necrosis factor-α (TNFα) in the adipose tissues. Importantly, consistent with the observed changes in the expression levels of marker genes for thermogenic adipocytes, combination treatment of clodronate liposome and cold exposure resulted in metabolic benefits such as lowered body weight and blood glucose level in obese mice. Moreover, intraperitoneal injection of recombinant TNFα protein suppressed UCP1 induction in lean adipose tissues of mice. Collectively, our data indicate that infiltrated M1 Mϕ suppress the induction of thermogenic adipocytes in obese adipose tissues via TNFα. This report suggests that inflammation induced by infiltrated Mϕ could cause not only insulin resistance but also reduction of energy expenditure in adipose tissues.
authors.affiliation: Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Uji, Kyoto University, Kyoto, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Sakamoto
authors.affiliation: Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Uji, Kyoto University, Kyoto, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nitta
authors.affiliation: Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Uji, Kyoto University, Kyoto, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Maruno
authors.affiliation: Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Uji, Kyoto University, Kyoto, Japan.
authors.forename: Yu-Sheng
authors.initials: YS
authors.lastname: Yeh
authors.affiliation: Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Uji, Kyoto University, Kyoto, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Kuwata
authors.affiliation: Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, Aichi, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Tomita
authors.affiliation: Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Uji, Kyoto University, Kyoto, Japan.|Research Unit for Physiological Chemistry, Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Goto
authors.affiliation: Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Uji, Kyoto University, Kyoto, Japan.|Research Unit for Physiological Chemistry, Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Uji, Kyoto University, Kyoto, Japan; fat@kais.kyoto-u.ac.jp.|Research Unit for Physiological Chemistry, Center for the Promotion of Interdisciplinary Education and Research, Kyoto University, Kyoto, Japan.
authors.forename: Teruo
authors.initials: T
authors.lastname: Kawada
mesh_terms: D000069797:Adipocytes, Beige / Q000187:drug effects / Q000378:metabolism; D052437:Adipocytes, Brown / Q000187:drug effects / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D004002:Clodronic Acid / Q000494:pharmacology; D003080:Cold Temperature; D059305:Diet, High-Fat; D004734:Energy Metabolism / Q000276:immunology; D015151:Immunoblotting; D007150:Immunohistochemistry; D007333:Insulin Resistance / Q000276:immunology*; D008081:Liposomes; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000276:immunology / Q000378:metabolism*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D022722:Thermogenesis; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D000071256:Uncoupling Protein 1 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism
chemical_list: D008081:Liposomes; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D004002:Clodronic Acid
keywords: inflammation; macrophage; mitochondrial biogenesis; thermogenic adipocyte; tumor necrosis factor-α; uncoupling protein 1