Glycolytic Stimulation Is Not a Requirement for M2 Macrophage Differentiation

Cell Metab. 2018 Sep 4;28(3):463-475.e4. doi: 10.1016/j.cmet.2018.08.012.


Enhanced glucose uptake and a switch to glycolysis are key traits of M1 macrophages, whereas enhanced fatty acid oxidation and oxidative phosphorylation are the main metabolic characteristics of M2 macrophages. Recent studies challenge this traditional view, indicating that glycolysis may also be critically important for M2 macrophage differentiation, based on experiments with 2-DG. Here we confirm the inhibitory effect of 2-DG on glycolysis, but also demonstrate that 2-DG impairs oxidative phosphorylation and significantly reduces 13C-labeled Krebs cycle metabolites and intracellular ATP levels. These metabolic derangements were associated with reduced JAK-STAT6 pathway activity and M2 differentiation marker expression. While glucose deprivation and glucose substitution with galactose effectively suppressed glycolytic activity, there was no effective suppression of oxidative phosphorylation, intracellular ATP levels, STAT6 phosphorylation, and M2 differentiation marker expression. These data indicate that glycolytic stimulation is not required for M2 macrophage differentiation as long as oxidative phosphorylation remains active.

Keywords: 2-DG; M2 macrophage; alternative stimulation; glucose; glycolysis; interleukin-4; metabolism.

Publication types

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

MeSH terms

  • Animals
  • Cell Differentiation / drug effects*
  • Cell Line
  • Citric Acid Cycle / drug effects
  • Deoxyglucose / pharmacology*
  • Glucose* / analogs & derivatives
  • Glucose* / metabolism
  • Glycolysis / drug effects*
  • Janus Kinases / metabolism
  • Macrophage Activation / drug effects*
  • Macrophages / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Oxidative Phosphorylation / drug effects*
  • STAT6 Transcription Factor / metabolism
  • Signal Transduction / drug effects


  • STAT6 Transcription Factor
  • Stat6 protein, mouse
  • Deoxyglucose
  • Janus Kinases
  • Glucose