Depletion of H2S during obesity enhances store-operated Ca2+ entry in adipose tissue macrophages to increase cytokine production

Sci Signal. 2015 Dec 15;8(407):ra128. doi: 10.1126/scisignal.aac7135.


The increased production of proinflammatory cytokines by adipose tissue macrophages (ATMs) contributes to chronic, low-level inflammation during obesity. We found that obesity in mice reduced the bioavailability of the gaseous signaling molecule hydrogen sulfide (H2S). Steady-state, intracellular concentrations of H2S were lower in ATMs isolated from mice with diet-induced obesity than in ATMs from lean mice. In addition, the intracellular concentration of H2S in the macrophage cell line RAW264.7 was reduced during an acute inflammatory response evoked by the microbial product lipopolysaccharide (LPS). Reduced intracellular concentrations of H2S led to increased Ca(2+) influx through the store-operated Ca(2+) entry (SOCE) pathway, which was prevented by the exogenous H2S donor GYY4137. Furthermore, GYY4137 inhibited the Orai3 channel, a key component of the SOCE machinery. The enhanced production of proinflammatory cytokines by RAW264.7 cells and ATMs from obese mice was reduced by exogenous H2S or by inhibition of SOCE. Together, these data suggest that the depletion of macrophage H2S that occurs during acute (LPS-induced) or chronic (obesity) inflammation increases SOCE through disinhibition of Orai3 and promotes the production of proinflammatory cytokines.

Publication types

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

MeSH terms

  • Adipose Tissue / metabolism*
  • Adipose Tissue / pathology
  • Animals
  • Calcium Channels / metabolism
  • Calcium Signaling*
  • Cell Line
  • Cytokines / metabolism*
  • Hydrogen Sulfide / metabolism*
  • Lipopolysaccharides / toxicity
  • Macrophages, Peritoneal / metabolism*
  • Macrophages, Peritoneal / pathology
  • Male
  • Mice
  • Morpholines / pharmacology
  • Obesity / metabolism*
  • Obesity / pathology
  • Organothiophosphorus Compounds / pharmacology


  • Calcium Channels
  • Cytokines
  • GYY 4137
  • Lipopolysaccharides
  • Morpholines
  • Orai3 protein, mouse
  • Organothiophosphorus Compounds
  • Hydrogen Sulfide