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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism
  • Adipose Tissue / metabolism*
  • Animals
  • Antigens, Surface / metabolism
  • Autophagy / drug effects
  • Cell Membrane / metabolism
  • Cells, Cultured
  • Culture Media, Conditioned / pharmacology
  • Glucose / pharmacology
  • Humans
  • Inflammation / metabolism
  • Insulin / pharmacology
  • Lipid Metabolism / physiology
  • Macrophages / drug effects
  • Macrophages / immunology
  • Macrophages / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Monocytes / cytology
  • PPAR gamma / metabolism
  • Palmitates / pharmacology
  • Phenotype


  • Adaptor Proteins, Signal Transducing
  • Antigens, Surface
  • Culture Media, Conditioned
  • Insulin
  • PPAR gamma
  • Palmitates
  • Glucose