title: Adipocyte lipolysis-stimulated interleukin-6 production requires sphingosine kinase 1 activity.
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.
authors.affiliation: Departments of Pathology, Wayne State University, Detroit, Michigan 48202; Departments of Bioactive Lipid Research Program, Wayne State University, Detroit, Michigan 48202.
authors.forename: Wenliang
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Departments of Pathology, Wayne State University, Detroit, Michigan 48202; Center for Integrative Metabolic and Endocrine Research, Wayne State University, Detroit, Michigan 48202.
authors.forename: Emilio P
authors.initials: EP
authors.lastname: Mottillo
authors.affiliation: Departments of Pathology, Wayne State University, Detroit, Michigan 48202; Departments of Bioactive Lipid Research Program, Wayne State University, Detroit, Michigan 48202.
authors.forename: Jiawei
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Departments of Pathology, Wayne State University, Detroit, Michigan 48202; Departments of Bioactive Lipid Research Program, Wayne State University, Detroit, Michigan 48202.
authors.forename: Allison
authors.initials: A
authors.lastname: Gartung
authors.affiliation: Department of Chemistry, Wayne State University, Detroit, Michigan 48202.
authors.forename: Garrett C
authors.initials: GC
authors.lastname: VanHecke
authors.affiliation: Departments of Pathology, Wayne State University, Detroit, Michigan 48202; Departments of Bioactive Lipid Research Program, Wayne State University, Detroit, Michigan 48202.
authors.forename: Jen-Fu
authors.initials: JF
authors.lastname: Lee
authors.affiliation: Departments of Pathology, Wayne State University, Detroit, Michigan 48202; Departments of Bioactive Lipid Research Program, Wayne State University, Detroit, Michigan 48202.
authors.forename: Krishna R
authors.initials: KR
authors.lastname: Maddipati
authors.affiliation: Department of Medicine, Alpert Medical School of Brown University, Providence, Rhode Island 02912, and.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Chemistry, Wayne State University, Detroit, Michigan 48202.
authors.forename: Young-Hoon
authors.initials: YH
authors.lastname: Ahn
authors.affiliation: Genetics of Development and Disease Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20814.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Proia
authors.affiliation: 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: jgranne@med.wayne.edu.
authors.forename: James G
authors.initials: JG
authors.lastname: Granneman
authors.affiliation: 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: Menqjer.lee@wayne.edu.
authors.forename: Menq-Jer
authors.initials: MJ
authors.lastname: Lee
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D000818:Animals; D007249:Inflammation / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D008066:Lipolysis; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D013107:Sphingolipids / Q000737:chemistry; D053719:Tandem Mass Spectrometry; D000099157:Sphingosine Kinase
chemical_list: D015850:Interleukin-6; D048670:MAP Kinase Kinase 4; D017853:Phosphotransferases (Alcohol Group Acceptor); D034741:RNA, Small Interfering; D013107:Sphingolipids; D000099157:Sphingosine Kinase; C577686:interleukin-6, mouse
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)