Adipocyte Lipolysis-stimulated Interleukin-6 Production Requires Sphingosine Kinase 1 Activity

• Published in: The Journal of biological chemistry Vol. 289; no. 46; pp. 32178 - 32185
• Main Authors: Zhang, Wenliang, Mottillo, Emilio P., Zhao, Jiawei, Gartung, Allison, VanHecke, Garrett C., Lee, Jen-Fu, Maddipati, Krishna R., Xu, Haiyan, Ahn, Young-Hoon, Proia, Richard L., Granneman, James G., Lee, Menq-Jer
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.11.2014; American Society for Biochemistry and Molecular Biology
• Subjects: 3T3-L1 Cells; Adipocytes - cytology; Adipocytes - metabolism; Adipose Tissue - metabolism; Adipose Tissue - pathology; Animals; Inflammation - metabolism; Interleukin-6 - metabolism; Lipids; Lipolysis; Male; MAP Kinase Kinase 4 - metabolism; Mice; Mice, Inbred C57BL; Phosphotransferases (Alcohol Group Acceptor) - metabolism; RNA, Small Interfering - metabolism; Signal Transduction; Sphingolipids - chemistry; Tandem Mass Spectrometry; Interleukin 6 (IL-6); Beta 3 Adrenergic Receptor; c-Jun N-terminal Kinase (JNK); AP1 Transcription Factor (AP-1); Inflammation; Adipose Tissue; Hormone-sensitive Lipase; Lipolysis; Sphingosine Kinase
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M114.601096

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.