Journal
CELL METABOLISM
Volume 20, Issue 4, Pages 614-625Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2014.08.010
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Funding
- National Institutes of Health [P30DK089507, RO1HL110879, R21CA143248, P30DK017047, P30CA015704]
- American Heart Association [10SDG3600027]
- American Diabetes Association [7-09-CT-36]
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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 PPARg 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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