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.
Wenliang Zhang  1 ,  Emilio P Mottillo  2 ,  Jiawei Zhao  1 ,  Allison Gartung  1 ,  Garrett C VanHecke  3 ,  Jen-Fu Lee  1 ,  Krishna R Maddipati  1 ,  Haiyan Xu  4 ,  Young-Hoon Ahn  3 ,  Richard L Proia  5 ,  James G Granneman  6 ,  Menq-Jer Lee  7
Affiliations
  • 1. Departments of Pathology, Wayne State University, Detroit, Michigan 48202; Departments of Bioactive Lipid Research Program, Wayne State University, Detroit, Michigan 48202.
  • 2. Departments of Pathology, Wayne State University, Detroit, Michigan 48202; Center for Integrative Metabolic and Endocrine Research, Wayne State University, Detroit, Michigan 48202.
  • 3. Department of Chemistry, Wayne State University, Detroit, Michigan 48202.
  • 4. Department of Medicine, Alpert Medical School of Brown University, Providence, Rhode Island 02912, and.
  • 5. Genetics of Development and Disease Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20814.
  • 6. Departments of Pathology, Wayne State University, Detroit, Michigan 48202; Center for Integrative Metabolic and Endocrine Research, Wayne State University, Detroit, Michigan 48202; Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan 48202. Electronic address: [email protected].
  • 7. Departments of Pathology, Wayne State University, Detroit, Michigan 48202; Departments of Bioactive Lipid Research Program, Wayne State University, Detroit, Michigan 48202; Karmanos Cancer Institute, and Wayne State University, Detroit, Michigan 48202; Cardiovascular Research Institute, Wayne State University, Detroit, Michigan 48202,. Electronic address: [email protected].
PMID: 25253697 DOI: 10.1074/jbc.M114.601096
Abstract

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).
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