Adipocyte Lipolysis Stimulated Interleukin-6 Production Requires Sphingosine kinase 1 activity [Signal Transduction]

September 24th, 2014 by Zhang, W., Mottillo, E. P., Zhao, J., Gartung, A., VanHecke, G. C., Lee, J.-F., Maddipati, K. R., Xu, H., Ahn, Y.-H., Proia, R. L., Granneman, J. G., Lee, M.-J.

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 (HSL). We report that stimulation of ADRB3 induces expression of sphingosine kinase 1 (SphK1) and increases S1P production in adipocytes in a manner that also depends on HSL activity. Mechanistically, we found that adipose lipolysis-induced SphK1 up-regulation is mediated by the c-Jun N-terminal kinase (JNK)/activating protein-1 (AP-1) signaling pathway. Inhibition of SphK1 by sphingosine kinase inhibitor 2 (SKI-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 knock down 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.