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Cell Rep. 2017 Sep 26;20(13):3149-3161. doi: 10.1016/j.celrep.2017.08.096.

Metabolically Activated Adipose Tissue Macrophages Perform Detrimental and Beneficial Functions during Diet-Induced Obesity.

Author information

1
Committee on Molecular Metabolism and Nutrition, The University of Chicago, Chicago, IL 60637, USA.
2
Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
3
Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA.
4
Cardiovascular Division, King's College, London British Hearth Foundation Centre, London SE5 9NU, UK.
5
Committee on Molecular Metabolism and Nutrition, The University of Chicago, Chicago, IL 60637, USA; Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
6
Committee on Molecular Metabolism and Nutrition, The University of Chicago, Chicago, IL 60637, USA; Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA. Electronic address: levb@uchicago.edu.

Abstract

During obesity, adipose tissue macrophages (ATMs) adopt a metabolically activated (MMe) phenotype. However, the functions of MMe macrophages are poorly understood. Here, we combine proteomic and functional methods to demonstrate that, in addition to potentiating inflammation, MMe macrophages promote dead adipocyte clearance through lysosomal exocytosis. We identify NADPH oxidase 2 (NOX2) as a driver of the inflammatory and adipocyte-clearing properties of MMe macrophages and show that, compared to wild-type, Nox2-/- mice exhibit a time-dependent metabolic phenotype during diet-induced obesity. After 8 weeks of high-fat feeding, Nox2-/- mice exhibit attenuated ATM inflammation and mildly improved glucose tolerance. After 16 weeks of high-fat feeding, Nox2-/- mice develop severe insulin resistance, hepatosteatosis, and visceral lipoatrophy characterized by dead adipocyte accumulation and defective ATM lysosomal exocytosis, a phenotype reproduced in myeloid cell-specific Nox2-/- mice. Collectively, our findings suggest that MMe macrophages perform detrimental and beneficial functions whose contribution to metabolic phenotypes during obesity is determined by disease progression.

KEYWORDS:

adipocyte; inflammation; insulin resistance; macrophage; metabolic activation; obesity

PMID:
28954231
PMCID:
PMC5646237
DOI:
10.1016/j.celrep.2017.08.096
[Indexed for MEDLINE]
Free PMC Article

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