title: Metabolic dysfunction drives a mechanistically distinct proinflammatory phenotype in adipose tissue macrophages.
abstract: Adipose tissue macrophage (ATM)-driven inflammation plays a key role in insulin resistance; however, factors activating ATMs are poorly understood. Using a proteomics approach, we show that markers of classical activation are absent on ATMs from obese humans but are readily detectable on airway macrophages of patients with cystic fibrosis, a disease associated with chronic bacterial infection. Moreover, treating macrophages with glucose, insulin, and palmitate-conditions characteristic of the metabolic syndrome-produces a "metabolically activated" phenotype distinct from classical activation. Markers of metabolic activation are expressed by proinflammatory ATMs in obese humans/mice and are positively correlated with adiposity. Metabolic activation is driven by independent proinflammatory and anti-inflammatory pathways, which regulate balance between cytokine production and lipid metabolism. We identify PPARγ and p62/SQSTM1 as two key proteins that promote lipid metabolism and limit inflammation in metabolically activated macrophages. Collectively, our data provide important mechanistic insights into pathways that drive the metabolic-disease-specific phenotype of macrophages.
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Department of Epidemiology, University of Washington, Seattle, WA 98195, USA; Department of Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Kratz
authors.affiliation: Committee on Molecular Metabolism and Nutrition, Pritzker School of Medicine, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Brittney R
authors.initials: BR
authors.lastname: Coats
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA 98195, USA.
authors.forename: Katherine B
authors.initials: KB
authors.lastname: Hisert
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Derek
authors.initials: D
authors.lastname: Hagman
authors.affiliation: Department of Pediatrics, Pritzker School of Medicine, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Vesco
authors.initials: V
authors.lastname: Mutskov
authors.affiliation: Department of Pediatrics, Pritzker School of Medicine, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Eduard
authors.initials: E
authors.lastname: Peris
authors.affiliation: Department of Pediatrics, Pritzker School of Medicine, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Kelly Q
authors.initials: KQ
authors.lastname: Schoenfelt
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Jessica N
authors.initials: JN
authors.lastname: Kuzma
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Ilona
authors.initials: I
authors.lastname: Larson
authors.affiliation: Puget Sound Surgical Center, Edmonds, WA 98026, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Billing
authors.affiliation: Puget Sound Surgical Center, Edmonds, WA 98026, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Landerholm
authors.affiliation: Puget Sound Surgical Center, Edmonds, WA 98026, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Crouthamel
authors.affiliation: Department of Pediatrics, Pritzker School of Medicine, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: David
authors.initials: D
authors.lastname: Gozal
authors.affiliation: Department of Pathology, Pritzker School of Medicine, The University of Chicago, Chicago, IL 60637, USA.
authors.forename: Seungmin
authors.initials: S
authors.lastname: Hwang
authors.affiliation: Department of Medicine, University of Washington, Seattle, WA 98195, USA; Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
authors.forename: Pradeep K
authors.initials: PK
authors.lastname: Singh
authors.affiliation: Committee on Molecular Metabolism and Nutrition, Pritzker School of Medicine, The University of Chicago, Chicago, IL 60637, USA; Department of Pediatrics, Pritzker School of Medicine, The University of Chicago, Chicago, IL 60637, USA. Electronic address: levb@uchicago.edu.
authors.forename: Lev
authors.initials: L
authors.lastname: Becker
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D050356:Lipid Metabolism / Q000502:physiology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009000:Monocytes / Q000166:cytology; D047495:PPAR gamma / Q000378:metabolism; D010168:Palmitates / Q000494:pharmacology; D010641:Phenotype
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000954:Antigens, Surface; D017077:Culture Media, Conditioned; D007328:Insulin; D047495:PPAR gamma; D010168:Palmitates; D005947:Glucose