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Cell Metab. 2014 Oct 7;20(4):614-25. doi: 10.1016/j.cmet.2014.08.010. Epub 2014 Sep 18.

Metabolic dysfunction drives a mechanistically distinct proinflammatory phenotype in adipose tissue macrophages.

Author information

1
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.
2
Committee on Molecular Metabolism and Nutrition, Pritzker School of Medicine, The University of Chicago, Chicago, IL 60637, USA.
3
Department of Medicine, University of Washington, Seattle, WA 98195, USA.
4
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
5
Department of Pediatrics, Pritzker School of Medicine, The University of Chicago, Chicago, IL 60637, USA.
6
Puget Sound Surgical Center, Edmonds, WA 98026, USA.
7
Department of Pathology, Pritzker School of Medicine, The University of Chicago, Chicago, IL 60637, USA.
8
Department of Medicine, University of Washington, Seattle, WA 98195, USA; Department of Microbiology, University of Washington, Seattle, WA 98195, USA.
9
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.

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.

PMID:
25242226
PMCID:
PMC4192131
DOI:
10.1016/j.cmet.2014.08.010
[Indexed for MEDLINE]
Free PMC Article

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