title: Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat.
abstract: Beige fat, which expresses the thermogenic protein UCP1, provides a defense against cold and obesity. Although a cold environment is the physiologic stimulus for inducing beige fat in mice and humans, the events that lead from the sensing of cold to the development of beige fat remain poorly understood. Here, we identify the efferent beige fat thermogenic circuit, consisting of eosinophils, type 2 cytokines interleukin (IL)-4/13, and alternatively activated macrophages. Genetic loss of eosinophils or IL-4/13 signaling impairs cold-induced biogenesis of beige fat. Mechanistically, macrophages recruited to cold-stressed subcutaneous white adipose tissue (scWAT) undergo alternative activation to induce tyrosine hydroxylase expression and catecholamine production, factors required for browning of scWAT. Conversely, administration of IL-4 to thermoneutral mice increases beige fat mass and thermogenic capacity to ameliorate pre-established obesity. Together, our findings have uncovered the efferent circuit controlling biogenesis of beige fat and provide support for its targeting to treat obesity.
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158-9001, USA.
authors.forename: Yifu
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158-9001, USA.
authors.forename: Khoa D
authors.initials: KD
authors.lastname: Nguyen
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158-9001, USA.
authors.forename: Justin I
authors.initials: JI
authors.lastname: Odegaard
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158-9001, USA.
authors.forename: Xiaojin
authors.initials: X
authors.lastname: Cui
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158-9001, USA.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Tian
authors.affiliation: Departments of Medicine and Microbiology and Immunology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158-9001, USA; Howard Hughes Medical Institute, Department of Biochemistry, University of Washington, Seattle, WA 98195-7350, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Locksley
authors.affiliation: Howard Hughes Medical Institute, Department of Biochemistry, University of Washington, Seattle, WA 98195-7350, USA.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Palmiter
authors.affiliation: Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158-9001, USA; Departments of Physiology and Medicine, University of California, San Francisco, San Francisco, CA 94158-9001, USA. Electronic address: ajay.chawla@ucsf.edu.
authors.forename: Ajay
authors.initials: A
authors.lastname: Chawla
mesh_terms: D052437:Adipocytes, Brown / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000378:metabolism*; D000818:Animals; D002395:Catecholamines / Q000378:metabolism; D003080:Cold Temperature; D004804:Eosinophils / Q000378:metabolism*; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism*; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000378:metabolism; D009765:Obesity / Q000378:metabolism; D054390:Receptors, CCR2 / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D022722:Thermogenesis
chemical_list: D002395:Catecholamines; C515335:Ccr2 protein, mouse; D018793:Interleukin-13; D054390:Receptors, CCR2; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015847:Interleukin-4