Adipocyte lipolysis-stimulated interleukin-6 production requires sphingosine kinase 1 activity
Open accessAbstract
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.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
ADRB3 agonist CL316,243, but not ADRB1/2 agonist isoproterenol, was sufficient to induce IL6.
“We thus challenged animals with ADRB agonists and found that the ADRB3 agonist CL316,243, but not the ADRB1/2 agonist isoproterenol, was sufficient to induce IL6 (Figure 3E and F), consistent with previous reports (Kosteli et al., 2010; Zhang et al., 2014).”
From Origin and function of stress-induced IL-6 in murine models (2020) · cites this paper as Zhang et al., 2014
Cites
Prevalence and trends in obesity among US adults, 1999–2000
Flegal, K. M. (2002) · JAMA · doi:10.1001/jama.288.14.1723 · Cited by 6,190 · see citing works
Overweight and obesity in the United States: prevalence and trends, 1960–1994
Flegal, K., Carroll, M., Kuczmarski, R., & Johnson, C. (1998) · International Journal of Obesity · doi:10.1038/sj.ijo.0800541 · Cited by 3,045 · see citing works
Elevated C-reactive protein levels in overweight and obese adults
Visser, M. (1999) · JAMA · doi:10.1001/jama.282.22.2131 · Cited by 2,494 · see citing works
Subcutaneous Adipose Tissue Releases Interleukin-6, But Not Tumor Necrosis Factor-α,in Vivo1
Mohamed‐Ali, V., Goodrick, S., Rawesh, A., Katz, D. R., Miles, J. M., Yudkin, J. S., Klein, S., & Coppack, S. W. (1997) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.82.12.4450 · Cited by 2,012 · see citing works
Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes
Esser, N., Legrand-Poels, S., Piette, J., Scheen, A. J., & Paquot, N. (2014) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2014.04.006 · Cited by 1,981 · see citing works
Interleukin-6 and chronic inflammation
Gabay, C. (2006) · Arthritis Research & Therapy · doi:10.1186/ar1917 · Cited by 1,468 · see citing works
Bastard, J., Jardel, C., Bruckert, É., Blondy, P., Capeau, J., Laville, M., Vidal, H., & Hainque, B. (2000) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.85.9.6839 · Cited by 1,102 · see citing works
Makki, K., Froguel, P., & Wolowczuk, I. (2013) · ISRN Inflammation · doi:10.1155/2013/139239 · Cited by 1,085 · see citing works
Sphingosine-1-Phosphate as a Ligand for the G Protein-Coupled Receptor EDG-1
Lee, M.-J., Brocklyn, J. R. V., Thangada, S., Liu, C. H., Hand, A. R., Menzeleev, R., Spiegel, S., & Hla, T. (1998) · Science · doi:10.1126/science.279.5356.1552 · Cited by 1,007 · see citing works
Self-citationRegulation of histone acetylation in the nucleus by sphingosine-1-phosphate
Hait, N. C., Allegood, J., Maceyka, M., Strub, G. M., Harikumar, K. B., Singh, S. K., Luo, C., Marmorstein, R., Kordula, T., Milstien, S., et al. (2009) · Science · doi:10.1126/science.1176709 · Cited by 997 · see citing works
Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2
Alvarez, S. E., Harikumar, K. B., Hait, N. C., Allegood, J. C., Strub, G. M., Kim, E. Y., Maceyka, M. W., Jiang, H., Luo, C., Kordula, T., et al. (2010) · Nature · doi:10.1038/nature09128 · Cited by 754 · see citing works
Obesity and Cardiovascular Disease
Poirier, P., Giles, T. D., Bray, G. A., Hong, Y., Stern, J. S., Pi-Sunyer, X., & Eckel, R. H. (2006) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000216787.85457.f3 · Cited by 726 · see citing works
A Stress Signaling Pathway in Adipose Tissue Regulates Hepatic Insulin Resistance
Sabio, G., Das, M., Mora, A., Zhang, Z., Jun, J. Y., Ko, H. J., Barrett, T., Kim, J. K., & Davis, R. J. (2008) · Science · doi:10.1126/science.1160794 · Cited by 604 · see citing works
Mice Deficient in Sphingosine Kinase 1 Are Rendered Lymphopenic by FTY720
Allende, M. L., Sasaki, T., Kawai, H., Olivera, A., Mi, Y., van Echten‐Deckert, G., Hajdu, R., Rosenbach, M. J., Keohane, C. A., MANDALA, S. M., et al. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m406512200 · Cited by 448 · see citing works
Self-citationBioactive Lysophospholipids and Their G Protein-Coupled Receptors
Moolenaar, W. H. (1999) · Experimental Cell Research · doi:10.1006/excr.1999.4702 · Cited by 412 · see citing works
Granneman, J. G., Li, P., Zhu, Z., & Lu, Y. (2005) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00009.2005 · Cited by 298 · see citing works
Self-citationLee, M.-J., Thangada, S., Paik, J.-H., Sapkota, G. P., Ancellin, N., Chae, S.-S., Wu, M.-T., Morales‐Ruiz, M., Sessa, W. C., Alessi, D. R., et al. (2001) · Molecular Cell · doi:10.1016/s1097-2765(01)00324-0 · Cited by 288 · see citing works
Self-citationDendritic cell PAR1–S1P3 signalling couples coagulation and inflammation
Niessen, F., Schaffner, F., Furlan-Freguia, C., Pawliński, R., Bhattacharjee, G., Chun, J. J. M., Derian, C. K., Andrade‐Gordon, P., Rosen, H., & Ruf, W. (2008) · Nature · doi:10.1038/nature06663 · Cited by 281 · see citing works
Antitumor Activity of Sphingosine Kinase Inhibitors
French, K. J., Upson, J. J., Keller, S. N., et al. (2006) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.106.101345 · Cited by 242 · see citing works
Engeland, A. (2003) · American Journal of Epidemiology · doi:10.1093/aje/kwf219 · Cited by 240 · see citing works
Eckel, R. H., York, D. A., Rössner, S., Hubbard, V. S., Caterson, I. D., Jeor, S. T. S., Hayman, L. L., Mullis, R. M., & Blair, S. N. (2004) · Circulation · doi:10.1161/01.cir.0000140086.88453.9a · Cited by 219 · see citing works
Mottillo, E. P., Bloch, A. E., Leff, T., & Granneman, J. G. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.374041 · Cited by 200 · see citing works
Self-citationJiao, P., Ma, J., Feng, B., Zhang, H., Diehl, J. A., Eugene‐Chin, Y., Yan, W., & Xu, H. (2010) · Obesity · doi:10.1038/oby.2010.200 · Cited by 197 · see citing works
Self-citationSphingosine 1-phosphate: a prototype of a new class of second messengers
Spiegel, S. (1999) · Journal of Leukocyte Biology · doi:10.1002/jlb.65.3.341 · Cited by 177 · see citing works
Skoura, A., Michaud, J. E., Im, D., Thangada, S., Xiong, Y., Smith, J. D., & Hla, T. (2010) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.110.213496 · Cited by 171 · see citing works
Szczepankiewicz, B. G., Kosogof, C., Nelson, L. T. J., Liu, G., Liu, B., Zhao, H., Serby, M. D., Xin, Z., Liu, M., Gum, R. J., et al. (2006) · Journal of Medicinal Chemistry · doi:10.1021/jm060199b · Cited by 163 · see citing works
Hla, T., Lee, M. J., Ancellin, N., et al. (1999) · Biochemical Pharmacology · doi:10.1016/s0006-2952(99)00086-6 · Cited by 153 · see citing works
Self-citationInflamed adipose tissue, insulin resistance and vascular injury
Andersson, C. X., Gustafson, B., Hammarstedt, A., Hedjazifar, S., & Smith, U. (2008) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.889 · Cited by 116 · see citing works
Sphingosine kinase 1 regulates adipose proinflammatory responses and insulin resistance
Wang, J., Badeanlou, L., Bielawski, J., Ciaraldi, T. P., & Samad, F. (2014) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00549.2013 · Cited by 101 · see citing works
Mottillo, E. P., Shen, X., & Granneman, J. G. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2010.04.012 · Cited by 93 · see citing works
Self-citationFrost, D. B., Barth, J. L., Chang, R. C., Obeid, L. M., & Gilkeson, G. S. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1000644 · Cited by 90 · see citing works
Specific Inhibition of Hormone-Sensitive Lipase Improves Lipid Profile while Reducing Plasma Glucose
Claus, T. H., Lowe, D., Liang, Y. T., Salhanick, A. I., Lubeski, C. K., Yang, L., Lemoine, L., Zhu, J., & Clairmont, K. B. (2005) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.105.086926 · Cited by 89 · see citing works
Hormone‐sensitive lipase (HSL) is also a retinyl ester hydrolase: evidence from mice lacking HSL
Ström, K., Gundersen, T. E., Hansson, O., Lucas, S., Fernandez, C., Blomhoff, R., & Holm, C. (2009) · The FASEB Journal · doi:10.1096/fj.08-120923 · Cited by 89 · see citing works
Hu, W. M., Bielawski, J., Samad, F., Merrill, A. H., & Cowart, L. A. (2009) · Journal of Lipid Research · doi:10.1194/jlr.m800635-jlr200 · Cited by 87 · see citing works
Role of hormone-sensitive lipase in β-adrenergic remodeling of white adipose tissue
Mottillo, E. P., Shen, X., & Granneman, J. G. (2007) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00051.2007 · Cited by 84 · see citing works
Self-citationRegulation of adipose tissue lipolysis revisited
Bézaire, V., & Langin, D. (2009) · Proceedings of The Nutrition Society · doi:10.1017/s0029665109990279 · Cited by 77 · see citing works
Igarashi, Y., & Yatomi, Y. (1998) · Acta Biochimica Polonica · doi:10.18388/abp.1998_4226 · Cited by 69 · see citing works
Mottillo, E. P., & Granneman, J. G. (2011) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00039.2011 · Cited by 61 · see citing works
Self-citationLee, M.-J. (2012) · International Journal of Oncology · doi:10.3892/ijo.2012.1379 · Cited by 58 · see citing works
Self-citationZhang, W., An, J., Jawadi, H., et al. (2013) · Prostaglandins & Other Lipid Mediators · doi:10.1016/j.prostaglandins.2013.06.001 · Cited by 57 · see citing works
Self-citationRoss, J. S., Hu, W. M., Rosen, B. P., Snider, A. J., Obeid, L. M., & Cowart, L. A. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.477786 · Cited by 53 · see citing works
The Evil Axis of Obesity, Inflammation and Type-2 Diabetes
Das, A., & Mukhopadhyay, S. (2011) · Endocrine Metabolic & Immune Disorders - Drug Targets · doi:10.2174/187153011794982086 · Cited by 49 · see citing works
Turpeinen, T., Nieminen, R. M., Moilanen, E., & Korhonen, R. (2010) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.109.157438 · Cited by 40 · see citing works
Ebdrup, S., Refsgaard, H. H. F., Fledelius, C., & Jacobsen, P. (2007) · Journal of Medicinal Chemistry · doi:10.1021/jm0607653 · Cited by 35 · see citing works
Bachmaier, K., Guzman, E., Kawamura, T., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0030742 · Cited by 29 · see citing works
Sphingolipids affect fibrinogen-induced caveolar transcytosis and cerebrovascular permeability
Muradashvili, N., Khundmiri, S. J., Tyagi, R., Gartung, A., Dean, W. L., Lee, M.-J., & Lominadze, D. G. (2014) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00305.2013 · Cited by 21 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Chait, A., & den Hartigh, L. J. (2020) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2020.00022 · Cited by 1,529 · see citing works
The endocrine function of adipose tissues in health and cardiometabolic disease
Scheja, L., & Heeren, J. (2019) · Nature Reviews Endocrinology · doi:10.1038/s41574-019-0230-6 · Cited by 663 · see citing works
Origin and function of stress-induced IL-6 in murine models
Qing, H., Desrouleaux, R., Israni-Winger, K., Mineur, Y. S., Fogelman, N., Zhang, C., Rashed, S., Palm, N. W., Sinha, R., Picciotto, M. R., et al. (2020) · Cell · doi:10.1016/j.cell.2020.05.054 · Cited by 303 · see citing works
Adipose tissue insulin action and IL-6 signaling after exercise in obese mice
MACPHERSON, R. E. K., HUBER, J. S., FRENDO-CUMBO, S., SIMPSON, J. A., & WRIGHT, D. C. (2015) · Medicine & Science in Sports & Exercise · doi:10.1249/mss.0000000000000660 · Cited by 62 · see citing works
Li, H., Liu, P., Deng, S., Zhu, L., Cao, X., Bao, X., Xia, S., Xu, Y., & Zhang, B. (2023) · Inflammation · doi:10.1007/s10753-023-01844-z · Cited by 43 · see citing works
- Authors
- 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.
- Affiliations
- Wayne State University (US)
- Brown University (US)
- National Institutes of Health (US)
- Corresponding author
- Granneman, James G.
- Lee, Menq-Jer
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2014-11
- Volume
- 289
- Issue
- 46
- Pages
- 32178-32185
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4231693
- OpenAlex
- W1973740991
- Cited by
- 80
- References
- 46
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 5 · 2023: 6 · 2022: 5 · 2021: 10 · 2020: 10 · 2019: 8 · 2018: 4 · 2017: 9 · 2016: 5 · 2015: 8 · 2014: 1
- FWCI
- 3.14
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (HL-071071, DK-076229, DK-062292, 5P600-DK020572)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- adipocyte lipolysis, interleukin-6, sphingosine kinase 1, sphingosine-1-phosphate, beta3-adrenergic receptor, hormone-sensitive lipase, c-Jun N-terminal kinase, AP-1 signaling, adipose tissue inflammation, insulin resistance
- MeSH terms
- Sphingosine Kinase, Adipose Tissue, Animals, Inflammation, Lipolysis, Male, Mice, Inbred C57BL, Sphingolipids, Signal Transduction, Interleukin-6, Adipocytes, Phosphotransferases (Alcohol Group Acceptor), RNA, Small Interfering, 3T3-L1 Cells, MAP Kinase Kinase 4, Mice, Tandem Mass Spectrometry
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
