title: Adipogenic role of alternatively activated macrophages in β-adrenergic remodeling of white adipose tissue.
abstract: De novo brown adipogenesis involves the proliferation and differentiation of progenitors, yet the mechanisms that guide these events in vivo are poorly understood. We previously demonstrated that treatment with a β3-adrenergic receptor (ADRB3) agonist triggers brown/beige adipogenesis in gonadal white adipose tissue following adipocyte death and clearance by tissue macrophages. The close physical relationship between adipocyte progenitors and tissue macrophages suggested that the macrophages that clear dying adipocytes might generate proadipogenic factors. Flow cytometric analysis of macrophages from mice treated with CL 316,243 identified a subpopulation that contained elevated lipid and expressed CD44. Lipidomic analysis of fluorescence-activated cell sorting-isolated macrophages demonstrated that CD44+ macrophages contained four- to five-fold higher levels of the endogenous peroxisome-proliferator activated receptor gamma (PPARγ) ligands 9-hydroxyoctadecadienoic acid (HODE), and 13-HODE compared with CD44- macrophages. Gene expression profiling and immunohistochemistry demonstrated that ADRB3 agonist treatment upregulated expression of ALOX15, the lipoxygenase responsible for generating 9-HODE and 13-HODE. Using an in vitro model of adipocyte efferocytosis, we found that IL-4-primed tissue macrophages accumulated lipid from dying fat cells and upregulated expression of Alox15. Furthermore, treatment of differentiating adipocytes with 9-HODE and 13-HODE potentiated brown/beige adipogenesis. Collectively, these data indicate that noninflammatory removal of adipocyte remnants and coordinated generation of PPARγ ligands by M2 macrophages provides localized adipogenic signals to support de novo brown/beige adipogenesis.
authors.affiliation: College of Pharmacy, Yonsei University, Incheon, South Korea;
authors.forename: Yun-Hee
authors.initials: YH
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Yonsei University, Incheon, South Korea;
authors.forename: Sang-Nam
authors.initials: SN
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Yonsei University, Incheon, South Korea;
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: Kwon
authors.affiliation: Lipidomics Core Facility and Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan; and.
authors.forename: Krishna Rao
authors.initials: KR
authors.lastname: Maddipati
authors.affiliation: Center for Integrative Metabolic and Endocrine Research, Wayne State University School of Medicine, Detroit, Michigan jgranne@med.wayne.edu.
authors.forename: James G
authors.initials: JG
authors.lastname: Granneman
mesh_terms: D052437:Adipocytes, Brown / Q000187:drug effects / Q000378:metabolism; D052438:Adipocytes, White / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D050156:Adipogenesis / Q000187:drug effects*; D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism; D052436:Adipose Tissue, White / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D058667:Adrenergic beta-3 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics / Q000378:metabolism; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000378:metabolism; D002450:Cell Communication / Q000187:drug effects*; D016923:Cell Death; D002460:Cell Line; D002469:Cell Separation / Q000379:methods; D018920:Coculture Techniques; D004149:Dioxoles / Q000494:pharmacology*; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects; D010641:Phenotype; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D058667:Adrenergic beta-3 Receptor Agonists; C476399:Cd44 protein, mouse; D004149:Dioxoles; D018960:Hyaluronan Receptors; D008024:Ligands; D047495:PPAR gamma; C076126:disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate; C521960:Alox15 protein, mouse; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase
keywords: adipogenesis; adipose tissue macrophages; beige adipocytes; brown adipocytes; phagocytosis