title: Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity.
abstract: Obesity is associated with infiltration of macrophages into adipose tissue (AT), contributing to insulin resistance and diabetes. However, relatively little is known regarding the origin of AT macrophages (ATMs). We discovered that murine models of obesity have prominent monocytosis and neutrophilia, associated with proliferation and expansion of bone marrow (BM) myeloid progenitors. AT transplantation conferred myeloid progenitor proliferation in lean recipients, while weight loss in both mice and humans (via gastric bypass) was associated with a reversal of monocytosis and neutrophilia. Adipose S100A8/A9 induced ATM TLR4/MyD88 and NLRP3 inflammasome-dependent IL-1β production. IL-1β interacted with the IL-1 receptor on BM myeloid progenitors to stimulate the production of monocytes and neutrophils. These studies uncover a positive feedback loop between ATMs and BM myeloid progenitors and suggest that inhibition of TLR4 ligands or the NLRP3-IL-1β signaling axis could reduce AT inflammation and insulin resistance in obesity.
authors.affiliation: Division of Preventive Medicine and Nutrition, Department of Medicine, Columbia University, New York, NY 10032, USA; Department of Internal Medicine, University of Kentucky, Lexington, KY 40514, USA.
authors.forename: Prabhakara R
authors.initials: PR
authors.lastname: Nagareddy
authors.affiliation: Haematopoiesis and Leukocyte Biology, Baker IDI Heart and Diabetes Institute, Melbourne VIC 3004, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Kraakman
authors.affiliation: Division of Inflammation, Walter and Eliza Hall Institute of Medical Research, Melbourne VIC 3052, Australia.
authors.forename: Seth L
authors.initials: SL
authors.lastname: Masters
authors.affiliation: Division of Preventive Medicine and Nutrition, Department of Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Roslynn A
authors.initials: RA
authors.lastname: Stirzaker
authors.affiliation: Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Gorman
authors.affiliation: Pennington Biomedical Research Institute, Louisiana State University, Baton Rouge, LA 70803, USA.
authors.forename: Ryan W
authors.initials: RW
authors.lastname: Grant
authors.affiliation: Haematopoiesis and Leukocyte Biology, Baker IDI Heart and Diabetes Institute, Melbourne VIC 3004, Australia.
authors.forename: Dragana
authors.initials: D
authors.lastname: Dragoljevic
authors.affiliation: Department of Medicine, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Eun Shil
authors.initials: ES
authors.lastname: Hong
authors.affiliation: Department of Internal Medicine, University of Kentucky, Lexington, KY 40514, USA.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Abdel-Latif
authors.affiliation: Department of Internal Medicine, University of Kentucky, Lexington, KY 40514, USA.
authors.forename: Susan S
authors.initials: SS
authors.lastname: Smyth
authors.affiliation: Department of Medicine, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Choi
authors.affiliation: Division of Endocrinology, Department of Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Judith
authors.initials: J
authors.lastname: Korner
authors.affiliation: Department of Medicine and Department of Pathology, University of Washington, Seattle, WA 98109, USA.
authors.forename: Karin E
authors.initials: KE
authors.lastname: Bornfeldt
authors.affiliation: Division of Cardiology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fisher
authors.affiliation: Pennington Biomedical Research Institute, Louisiana State University, Baton Rouge, LA 70803, USA; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Vishwa Deep
authors.initials: VD
authors.lastname: Dixit
authors.affiliation: Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY 10032, USA.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Tall
authors.affiliation: Division of Preventive Medicine and Nutrition, Department of Medicine, Columbia University, New York, NY 10032, USA; Division of Endocrinology, Diabetes and Metabolism, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Ira J
authors.initials: IJ
authors.lastname: Goldberg
authors.affiliation: Haematopoiesis and Leukocyte Biology, Baker IDI Heart and Diabetes Institute, Melbourne VIC 3004, Australia; Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY 10032, USA; Department of Immunology, Monash University, Melbourne VIC 3004, Australia. Electronic address: andrew.murphy@bakeridi.edu.au.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Murphy
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000502:physiology; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000378:metabolism*; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D038042:Myelopoiesis / Q000502:physiology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009504:Neutrophils / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D017472:Receptors, Interleukin-1; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4