Cell Metabolism
Volume 20, Issue 4, 7 October 2014, Pages 614-625
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Article
Metabolic Dysfunction Drives a Mechanistically Distinct Proinflammatory Phenotype in Adipose Tissue Macrophages

https://doi.org/10.1016/j.cmet.2014.08.010Get rights and content
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Highlights

  • Stimuli associated with metabolic disease promote macrophage metabolic activation

  • Metabolic activation involves distinct mechanisms and surface markers

  • ATMs of obese humans/mice overexpress metabolic activation markers, not M1 markers

  • Markers of metabolically activated macrophages are positively correlated with BMI

Summary

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.

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