MAFB in macrophages regulates cold-induced neuronal density in brown adipose tissue
Manoj Kumar Yadav,
Megumi Ishida,
Natalia Gogoleva,
Ching-Wei Liao,
Filiani Natalia Salim,
Maho Kanai,
Akihiro Kuno,
Takuto Hayashi,
Zeynab Javanfekr Shahri,
Kaushalya Kulathunga,
Omar Samir,
Wenxin Lyu,
Olivia Olivia,
Evaristus C. Mbanefo,
Satoru Takahashi,
Michito Hamada
Affiliations
Manoj Kumar Yadav
Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan; Ph.D. Program in Human Biology, School of Integrative and Global Majors, University of Tsukuba, Tsukuba 305-8575, Japan; National Institutes of Health, Bethesda, MD 20892, USA
Megumi Ishida
Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan
Natalia Gogoleva
Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan; Ph.D. Program in Human Biology, School of Integrative and Global Majors, University of Tsukuba, Tsukuba 305-8575, Japan
Ching-Wei Liao
Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan; Ph.D. Program in Human Biology, School of Integrative and Global Majors, University of Tsukuba, Tsukuba 305-8575, Japan
Filiani Natalia Salim
Centre for Medical Science and Technology and Healthcare Equity, Parahyangan Catholic University, Bandung 40141, Indonesia
Maho Kanai
Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan; Ph.D. Program in Human Biology, School of Integrative and Global Majors, University of Tsukuba, Tsukuba 305-8575, Japan
Akihiro Kuno
Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan
Takuto Hayashi
Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan; Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba 305-8575, Japan
Zeynab Javanfekr Shahri
Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan; Ph.D. Program in Human Biology, School of Integrative and Global Majors, University of Tsukuba, Tsukuba 305-8575, Japan
Kaushalya Kulathunga
Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan; Ph.D. Program in Human Biology, School of Integrative and Global Majors, University of Tsukuba, Tsukuba 305-8575, Japan
Omar Samir
Department of Pathology, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Egypt; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Jeff and Penny Vinik Center for Allergic Disease Research, Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, Boston, MA 02115, USA
Wenxin Lyu
Ph.D. Program in Human Biology, School of Integrative and Global Majors, University of Tsukuba, Tsukuba 305-8575, Japan; Department of Immunology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan; Department of Immunology and Microbiology, LEO Foundation Skin Immunology Research Center, University of Copenhagen, 2200 Copenhagen, Denmark
Olivia Olivia
Faculty of Medicine, Universitas Padjadjaran, Sumedang 45363, Indonesia
Evaristus C. Mbanefo
National Institutes of Health, Bethesda, MD 20892, USA
Satoru Takahashi
Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan; Laboratory Animal Resource Center (LARC), Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba 305-8575, Japan; Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance, University of Tsukuba, Tsukuba 305-8575, Japan; Corresponding author
Michito Hamada
Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan; Laboratory Animal Resource Center (LARC), Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan; Corresponding author
Summary: Transcription factor MAFB regulates various homeostatic functions of macrophages. This study explores the role of MAFB in brown adipose tissue (BAT) thermogenesis using macrophage-specific Mafb-deficient (Mafbf/f::LysM-Cre) mice. We find that Mafb deficiency in macrophages reduces thermogenesis, energy expenditure, and sympathetic neuron (SN) density in BAT under cold conditions. This phenotype features a proinflammatory environment that is characterized by macrophage/granulocyte accumulation, increases in interleukin-6 (IL-6) production, and IL-6 trans-signaling, which lead to decreases in nerve growth factor (NGF) expression and reduction in SN density in BAT. We confirm MAFB regulation of IL-6 expression using luciferase readout driven by IL-6 promoter in RAW-264.7 macrophage cell lines. Immunohistochemistry shows clustered organization of NGF-producing cells in BAT, which are primarily TRPV1+ vascular smooth muscle cells, as additionally shown using single-cell RNA sequencing and RT-qPCR of the stromal vascular fraction. Treating Mafbf/f::LysM-Cre mice with anti-IL-6 receptor antibody rescues SN density, body temperature, and energy expenditure.
