title: Characterization of distinct subpopulations of hepatic macrophages in HFD/obese mice.
abstract: The current dogma is that obesity-associated hepatic inflammation is due to increased Kupffer cell (KC) activation. However, recruited hepatic macrophages (RHMs) were recently shown to represent a sizable liver macrophage population in the context of obesity. Therefore, we assessed whether KCs and RHMs, or both, represent the major liver inflammatory cell type in obesity. We used a combination of in vivo macrophage tracking methodologies and adoptive transfer techniques in which KCs and RHMs are differentially labeled with fluorescent markers. With these approaches, the inflammatory phenotype of these distinct macrophage populations was determined under lean and obese conditions. In vivo macrophage tracking revealed an approximately sixfold higher number of RHMs in obese mice than in lean mice, whereas the number of KCs was comparable. In addition, RHMs comprised smaller size and immature, monocyte-derived cells compared with KCs. Furthermore, RHMs from obese mice were more inflamed and expressed higher levels of tumor necrosis factor-α and interleukin-6 than RHMs from lean mice. A comparison of the MCP-1/C-C chemokine receptor type 2 (CCR2) chemokine system between the two cell types showed that the ligand (MCP-1) is more highly expressed in KCs than in RHMs, whereas CCR2 expression is approximately fivefold greater in RHMs. We conclude that KCs can participate in obesity-induced inflammation by causing the recruitment of RHMs, which are distinct from KCs and are not precursors to KCs. These RHMs then enhance the severity of obesity-induced inflammation and hepatic insulin resistance.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA.
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Morinaga
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA Networked Biomedical Research Center on Hepatic and Digestive Diseases (CIBERehd), Monforte de Lemos 3-5, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Mayoral
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA.
authors.forename: Jan
authors.initials: J
authors.lastname: Heinrichsdorff
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA.
authors.forename: Olivia
authors.initials: O
authors.lastname: Osborn
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA.
authors.forename: Niclas
authors.initials: N
authors.lastname: Franck
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA.
authors.forename: Nasun
authors.initials: N
authors.lastname: Hah
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Walenta
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA.
authors.forename: Gautam
authors.initials: G
authors.lastname: Bandyopadhyay
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA Institute of Biochemistry, Graz University of Technology, Graz, Austria.
authors.forename: Ariane R
authors.initials: AR
authors.lastname: Pessentheiner
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA.
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Chi
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA.
authors.forename: Heekyung
authors.initials: H
authors.lastname: Chung
authors.affiliation: Institute of Biochemistry, Graz University of Technology, Graz, Austria.
authors.forename: Juliane G
authors.initials: JG
authors.lastname: Bogner-Strauss
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA.
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA dayoungoh@ucsd.edu jolefsky@ucsd.edu.
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Olefsky
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA dayoungoh@ucsd.edu jolefsky@ucsd.edu.
authors.forename: Da Young
authors.initials: DY
authors.lastname: Oh
mesh_terms: D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology; D005943:Gluconeogenesis / Q000502:physiology*; D015850:Interleukin-6 / Q000378:metabolism; D007728:Kupffer Cells / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D054390:Receptors, CCR2 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C515335:Ccr2 protein, mouse; D015850:Interleukin-6; D054390:Receptors, CCR2; D014409:Tumor Necrosis Factor-alpha