Adipocyte lipolysis-stimulated interleukin-6 production requires sphingosine kinase 1 activity

J Biol Chem. 2014 Nov 14;289(46):32178-32185. doi: 10.1074/jbc.M114.601096. Epub 2014 Sep 24.


Adipocyte lipolysis can increase the production of inflammatory cytokines such as interleukin-6 (IL-6) that promote insulin resistance. However, the mechanisms that link lipolysis with inflammation remain elusive. Acute activation of β3-adrenergic receptors (ADRB3) triggers lipolysis and up-regulates production of IL-6 in adipocytes, and both of these effects are blocked by pharmacological inhibition of hormone-sensitive lipase. We report that stimulation of ADRB3 induces expression of sphingosine kinase 1 (SphK1) and increases sphingosine 1-phosphate production in adipocytes in a manner that also depends on hormone-sensitive lipase activity. Mechanistically, we found that adipose lipolysis-induced SphK1 up-regulation is mediated by the c-Jun N-terminal kinase (JNK)/activating protein-1 signaling pathway. Inhibition of SphK1 by sphingosine kinase inhibitor 2 diminished the ADRB3-induced IL-6 production both in vitro and in vivo. Induction of IL-6 by ADRB3 activation was suppressed by siRNA knockdown of Sphk1 in cultured adipocytes and was severely attenuated in Sphk1 null mice. Conversely, ectopic expression of SphK1 increased IL-6 expression in adipocytes. Collectively, these data demonstrate that SphK1 is a critical mediator in lipolysis-triggered inflammation in adipocytes.

Keywords: AP1 Transcription Factor (AP-1); Adipose Tissue; Beta 3 Adrenergic Receptor; Hormone-sensitive Lipase; Inflammation; Interleukin 6 (IL-6); Lipolysis; Sphingosine Kinase; c-Jun N-terminal Kinase (JNK).

Publication types

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

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / cytology*
  • Adipocytes / metabolism
  • Adipose Tissue / metabolism
  • Adipose Tissue / pathology
  • Animals
  • Inflammation / metabolism*
  • Interleukin-6 / metabolism*
  • Lipolysis*
  • MAP Kinase Kinase 4 / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • RNA, Small Interfering / metabolism
  • Signal Transduction
  • Sphingolipids / chemistry
  • Tandem Mass Spectrometry


  • Interleukin-6
  • RNA, Small Interfering
  • Sphingolipids
  • interleukin-6, mouse
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • MAP Kinase Kinase 4