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Link to original content: https://doi.org/10.1038/nm.2277
Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin | Nature Medicine
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Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin

Nature Medicine volume 17, pages 55–63 (2011)Cite this article

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Abstract

The adipocyte-derived secretory factor adiponectin promotes insulin sensitivity, decreases inflammation and promotes cell survival. No unifying mechanism has yet explained how adiponectin can exert such a variety of beneficial systemic effects. Here, we show that adiponectin potently stimulates a ceramidase activity associated with its two receptors, AdipoR1 and AdipoR2, and enhances ceramide catabolism and formation of its antiapoptotic metabolite—sphingosine-1-phosphate (S1P)—independently of AMP-dependent kinase (AMPK). Using models of inducible apoptosis in pancreatic beta cells and cardiomyocytes, we show that transgenic overproduction of adiponectin decreases caspase-8-mediated death, whereas genetic ablation of adiponectin enhances apoptosis in vivo through a sphingolipid-mediated pathway. Ceramidase activity is impaired in cells lacking both adiponectin receptor isoforms, leading to elevated ceramide levels and enhanced susceptibility to palmitate-induced cell death. Combined, our observations suggest a unifying mechanism of action for the beneficial systemic effects exerted by adiponectin, with sphingolipid metabolism as its core upstream signaling component.

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Figure 1: Adiponectin rapidly lowers hepatic ceramide content and improves glucose homeostasis.
Figure 2: Adiponectin promotes cardiomyocyte and HEART-ATTAC survival.
Figure 3: Adiponectin targets the endocrine pancreas and maintains beta cell mass.
Figure 4: Adiponectin alters sensitivity to ceramide-induced apoptosis in INS-1 beta cells.
Figure 5: Adiponectin receptors 1 and 2 confer ceramidase activity in vivo.
Figure 6: Ablating adiponectin receptors 1 and 2 impairs ceramidase activity, S1P generation and cell survival.

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References

  1. Yamauchi, T. et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 423, 762–769 (2003).

    Article  CAS  Google Scholar 

  2. Combs, T.P. et al. A transgenic mouse with a deletion in the collagenous domain of adiponectin displays elevated circulating adiponectin and improved insulin sensitivity. Endocrinology 145, 367–383 (2004).

    Article  CAS  Google Scholar 

  3. Kim, J.Y. et al. Obesity-associated improvements in metabolic profile through expansion of adipose tissue. J. Clin. Invest. 117, 2621–2637 (2007).

    Article  CAS  Google Scholar 

  4. Nawrocki, A.R. et al. Mice lacking adiponectin show decreased hepatic insulin sensitivity and reduced responsiveness to peroxisome proliferator-activated receptor gamma agonists. J. Biol. Chem. 281, 2654–2660 (2006).

    Article  CAS  Google Scholar 

  5. Kubota, N. et al. Disruption of adiponectin causes insulin resistance and neointimal formation. J. Biol. Chem. 277, 25863–25866 (2002).

    Article  CAS  Google Scholar 

  6. Yamauchi, T. et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat. Med. 8, 1288–1295 (2002).

    Article  CAS  Google Scholar 

  7. Yamauchi, T. et al. Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat. Med. 13, 332–339 (2007).

    Article  CAS  Google Scholar 

  8. Iwabu, M. et al. Adiponectin and AdipoR1 regulate PGC-1α and mitochondria by Ca2+ and AMPK/SIRT1. Nature 464, 1313–1319 (2010).

    Article  CAS  Google Scholar 

  9. Schraw, T., Wang, Z.V., Halberg, N., Hawkins, M. & Scherer, P.E. Plasma adiponectin complexes have distinct biochemical characteristics. Endocrinology 149, 2270–2282 (2008).

    Article  CAS  Google Scholar 

  10. Halberg, N. et al. Systemic fate of the adipocyte-derived factor adiponectin. Diabetes 58, 1961–1970 (2009).

    Article  Google Scholar 

  11. Merrill, A.H. Jr. De novo sphingolipid biosynthesis: a necessary, but dangerous, pathway. J. Biol. Chem. 277, 25843–25846 (2002).

    Article  CAS  Google Scholar 

  12. Holland, W.L. & Summers, S.A. Sphingolipids, insulin resistance, and metabolic disease: new insights from in vivo manipulation of sphingolipid metabolism. Endocr. Rev. 29, 381–402 (2008).

    Article  CAS  Google Scholar 

  13. Savage, D.B., Petersen, K.F. & Shulman, G.I. Disordered lipid metabolism and the pathogenesis of insulin resistance. Physiol. Rev. 87, 507–520 (2007).

    Article  CAS  Google Scholar 

  14. Kim, J.K. et al. PKC-theta knockout mice are protected from fat-induced insulin resistance. J. Clin. Invest. 114, 823–827 (2004).

    Article  CAS  Google Scholar 

  15. Yu, C. et al. Mechanism by which fatty acids inhibit insulin activation of IRS-1 associated phosphatidylinositol 3-kinase activity in muscle. J. Biol. Chem. 277, 50230–50236 (2002).

    Article  CAS  Google Scholar 

  16. Benoit, S.C. et al. Palmitic acid mediates hypothalamic insulin resistance by altering PKC-theta subcellular localization in rodents. J. Clin. Invest. 119, 2577–2589 (2009).

    Article  CAS  Google Scholar 

  17. Stratford, S., Hoehn, K.L., Liu, F. & Summers, S.A. Regulation of insulin action by ceramide: dual mechanisms linking ceramide accumulation to the inhibition of Akt/protein kinase B. J. Biol. Chem. 279, 36608–36615 (2004).

    Article  CAS  Google Scholar 

  18. Mukhopadhyay, A. et al. Direct interaction between the inhibitor 2 and ceramide via sphingolipid-protein binding is involved in the regulation of protein phosphatase 2A activity and signaling. FASEB J. 23, 751–763 (2009).

    Article  CAS  Google Scholar 

  19. Bourbon, N.A., Yun, J., Berkey, D., Wang, Y. & Kester, M. Inhibitory actions of ceramide upon PKC-epsilon/ERK interactions. Am. J. Physiol. Cell Physiol. 280, C1403–C1411 (2001).

    Article  CAS  Google Scholar 

  20. Powell, D.J., Hajduch, E., Kular, G. & Hundal, H.S. Ceramide disables 3-phosphoinositide binding to the pleckstrin homology domain of protein kinase B (PKB)/Akt by a PKCzeta-dependent mechanism. Mol. Cell. Biol. 23, 7794–7808 (2003).

    Article  CAS  Google Scholar 

  21. Fox, T.E. et al. Ceramide recruits and activates protein kinase C zeta (PKC zeta) within structured membrane microdomains. J. Biol. Chem. 282, 12450–12457 (2007).

    Article  CAS  Google Scholar 

  22. Takabe, K., Paugh, S.W., Milstien, S. & Spiegel, S. ″Inside-out″ signaling of sphingosine-1-phosphate: therapeutic targets. Pharmacol. Rev. 60, 181–195 (2008).

    Article  CAS  Google Scholar 

  23. Combs, T.P., Berg, A.H., Obici, S., Scherer, P.E. & Rossetti, L. Endogenous glucose production is inhibited by the adipose-derived protein Acrp30. J. Clin. Invest. 108, 1875–1881 (2001).

    Article  CAS  Google Scholar 

  24. Berg, A.H., Combs, T.P., Du, X., Brownlee, M. & Scherer, P.E. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat. Med. 7, 947–953 (2001).

    Article  CAS  Google Scholar 

  25. Pajvani, U.B. et al. Fat apoptosis through targeted activation of caspase 8: a new mouse model of inducible and reversible lipoatrophy. Nat. Med. 11, 797–803 (2005).

    Article  CAS  Google Scholar 

  26. Wang, Z.V. et al. PANIC-ATTAC: a mouse model for inducible and reversible beta-cell ablation. Diabetes 57, 2137–2148 (2008).

    Article  CAS  Google Scholar 

  27. Wencker, D. et al. A mechanistic role for cardiac myocyte apoptosis in heart failure. J. Clin. Invest. 111, 1497–1504 (2003).

    Article  CAS  Google Scholar 

  28. Brakch, N. et al. Evidence for a role of sphingosine-1 phosphate in cardiovascular remodelling in Fabry disease. Eur. Heart J. 31, 67–76 (2010).

    Article  CAS  Google Scholar 

  29. Gleason, C.E., Lu, D., Witters, L.A., Newgard, C.B. & Birnbaum, M.J. The role of AMPK and mTOR in nutrient sensing in pancreatic beta-cells. J. Biol. Chem. 282, 10341–10351 (2007).

    Article  CAS  Google Scholar 

  30. Mao, C. & Obeid, L.M. Ceramidases: regulators of cellular responses mediated by ceramide, sphingosine, and sphingosine-1-phosphate. Biochim. Biophys. Acta 1781, 424–434 (2008).

    Article  CAS  Google Scholar 

  31. Villa, N.Y. et al. Sphingolipids function as downstream effectors of a fungal PAQR. Mol. Pharmacol. 75, 866–875 (2009).

    Article  CAS  Google Scholar 

  32. Shaw, R.J. et al. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc. Natl. Acad. Sci. USA 101, 3329–3335 (2004).

    Article  CAS  Google Scholar 

  33. Holland, W.L. & Scherer, P.E. PAQRs: a counteracting force to ceramides? Mol. Pharmacol. 75, 740–743 (2009).

    Article  CAS  Google Scholar 

  34. Aerts, J.M. et al. Pharmacological inhibition of glucosylceramide synthase enhances insulin sensitivity. Diabetes 56, 1341–1349 (2007).

    Article  CAS  Google Scholar 

  35. Holland, W.L. et al. Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metab. 5, 167–179 (2007).

    Article  CAS  Google Scholar 

  36. Yamashita, T. et al. Enhanced insulin sensitivity in mice lacking ganglioside GM3. Proc. Natl. Acad. Sci. USA 100, 3445–3449 (2003).

    Article  CAS  Google Scholar 

  37. Zhao, H. et al. Inhibiting glycosphingolipid synthesis improves glycemic control and insulin sensitivity in animal models of type 2 diabetes. Diabetes 56, 1210–1218 (2007).

    Article  CAS  Google Scholar 

  38. El Bawab, S. et al. Substrate specificity of rat brain ceramidase. J. Lipid Res. 43, 141–148 (2002).

    CAS  PubMed  Google Scholar 

  39. Asterholm, I.W. & Scherer, P.E. Enhanced metabolic flexibility associated with elevated adiponectin levels. Am. J. Pathol. 176, 1364–1376 (2010).

    Article  CAS  Google Scholar 

  40. Puigserver, P. Tissue-specific regulation of metabolic pathways through the transcriptional coactivator PGC1-alpha. Int. J. Obes. (Lond.) 29 (suppl. 1), S5–S9 (2005).

    Article  CAS  Google Scholar 

  41. Levine, Y.C., Li, G.K. & Michel, T. Agonist-modulated regulation of AMP-activated protein kinase (AMPK) in endothelial cells. Evidence for an AMPK → Rac1 → Akt → endothelial nitric-oxide synthase pathway. J. Biol. Chem. 282, 20351–20364 (2007).

    Article  CAS  Google Scholar 

  42. Olivera, A. et al. The sphingosine kinase-sphingosine-1-phosphate axis is a determinant of mast cell function and anaphylaxis. Immunity 26, 287–297 (2007).

    Article  CAS  Google Scholar 

  43. Spiegel, S. & Milstien, S. Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat. Rev. Mol. Cell Biol. 4, 397–407 (2003).

    Article  CAS  Google Scholar 

  44. Hardie, D.G. AMPK: a key regulator of energy balance in the single cell and the whole organism. Int. J. Obes. (Lond.) 32 (suppl. 4), S7–S12 (2008).

    Article  CAS  Google Scholar 

  45. Karliner, J.S. Sphingosine kinase and sphingosine 1-phosphate in cardioprotection. J. Cardiovasc. Pharmacol. 53, 189–197 (2009).

    Article  CAS  Google Scholar 

  46. Van Veldhoven, P.P., Gijsbers, S., Mannaerts, G.P., Vermeesch, J.R. & Brys, V. Human sphingosine-1-phosphate lyase: cDNA cloning, functional expression studies and mapping to chromosome 10q22(1). Biochim. Biophys. Acta 1487, 128–134 (2000).

    Article  CAS  Google Scholar 

  47. Kupchak, B.R. et al. Probing the mechanism of FET3 repression by Izh2p overexpression. Biochim. Biophys. Acta 1773, 1124–1132 (2007).

    Article  CAS  Google Scholar 

  48. King, C.C. et al. Sphingosine is a novel activator of 3-phosphoinositide-dependent kinase 1. J. Biol. Chem. 275, 18108–18113 (2000).

    Article  CAS  Google Scholar 

  49. Clackson, T. et al. Redesigning an FKBP-ligand interface to generate chemical dimerizers with novel specificity. Proc. Natl. Acad. Sci. USA 95, 10437–10442 (1998).

    Article  CAS  Google Scholar 

  50. Pajvani, U.B. et al. Structure-function studies of the adipocyte-secreted hormone Acrp30/adiponectin. Implications for metabolic regulation and bioactivity. J. Biol. Chem. 278, 9073–9085 (2003).

    Article  CAS  Google Scholar 

  51. Li, Z. et al. Liver-specific deficiency of serine palmitoyltransferase subunit 2 decreases plasma sphingomyelin and increases apolipoprotein E levels. J. Biol. Chem. 284, 27010–27019 (2009).

    Article  CAS  Google Scholar 

  52. Perry, D.K., Bielawska, A. & Hannun, Y.A. Quantitative determination of ceramide using diglyceride kinase. Methods Enzymol. 312, 22–31 (2000).

    Article  CAS  Google Scholar 

  53. Berglund, E.D. et al. Fibroblast growth factor 21 controls glycemia via regulation of hepatic glucose flux and insulin sensitivity. Endocrinology 150, 4084–4093 (2009).

    Article  CAS  Google Scholar 

  54. Stein, D.T. et al. The insulinotropic potency of fatty acids is influenced profoundly by their chain length and degree of saturation. J. Clin. Invest. 100, 398–403 (1997).

    Article  CAS  Google Scholar 

  55. Mao, C. et al. Cloning and characterization of a novel human alkaline ceramidase. A mammalian enzyme that hydrolyzes phytoceramide. J. Biol. Chem. 276, 26577–26588 (2001).

    Article  CAS  Google Scholar 

  56. Mu, J., Brozinick, J.T. Jr. Valladares, O., Bucan, M. & Birnbaum, M.J. A role for AMP-activated protein kinase in contraction- and hypoxia-regulated glucose transport in skeletal muscle. Mol. Cell 7, 1085–1094 (2001).

    Article  CAS  Google Scholar 

  57. Burger, D. et al. Erythropoietin protects cardiomyocytes from apoptosis via up-regulation of endothelial nitric oxide synthase. Cardiovasc. Res. 72, 51–59 (2006).

    Article  CAS  Google Scholar 

  58. Hohmeier, H.E. et al. Isolation of INS-1-derived cell lines with robust ATP-sensitive K+ channel-dependent and -independent glucose-stimulated insulin secretion. Diabetes 49, 424–430 (2000).

    Article  CAS  Google Scholar 

  59. Hohmeier, H.E., Tran, V.V., Chen, G., Gasa, R. & Newgard, C.B. Inflammatory mechanisms in diabetes: lessons from the beta-cell. Int. J. Obes. Relat. Metab. Disord. 27 (suppl. 3), S12–S16 (2003).

    Article  CAS  Google Scholar 

  60. He, L. & Fox, M.H. Variation of heat shock protein 70 through the cell cycle in HL-60 cells and its relationship to apoptosis. Exp. Cell Res. 232, 64–71 (1997).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank members of the Scherer and Summers laboratories for comments. We would like to thank R. Kitsis for discussions regarding the generation of HEART-ATTAC mice. We thank B. Hammer and the Transgenic Core Facility at UT Southwestern for the generation of the mouse models used in this study and the Metabolic Core Facility at UT Southwestern for help with phenotyping of the mice. Lkb1−/− mice and cells were a kind gift from R. DePinho, Massachusetts General Hospital. INS-1 832/13 cells were generously provided by C. Newgard, Duke University Medical Center. We thank Ariad Pharmaceuticals for providing the dimerization kit and compound AP20187. This work was supported by US National Institutes of Health grants R01-DK55758, R01-CA112023, RC1-DK086629 and P01-DK088761 (P.E.S.); R01-DK56886 and P01-DK49210 (M.J.B.); as well as R21-DK073181 (S.A.S.). W.L.H. was supported by National Research Service Award F32-DK083866 and TL1-DK081181. J.M.R. was supported by F32-DK085935 and T32-HL007360 and K.E.D. was supported by F32-DK081279. N.H. was funded by a grant from University of Copenhagen.

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Authors and Affiliations

  1. Touchstone Diabetes Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA

    William L Holland, Zhao V Wang, Kai Sun, Kathryn E Davis, Nils Halberg, Joseph M Rutkowski, Vincent M Tenorio & Philipp E Scherer

  2. Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

    Russell A Miller & Morris J Birnbaum

  3. Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, Colorado, USA

    Brian M Barth & Scott A Summers

  4. Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, USA

    Hai H Bui, Mark R Wade, Ming-Shang Kuo & Joseph T Brozinick

  5. Program in Cardiovascular and Metabolic Diseases, Duke-National University of Singapore Graduate Medical School, Singapore

    Benjamin T Bikman & Scott A Summers

  6. Department of Biomedical Sciences, Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark

    Nils Halberg

  7. Department of Metabolic Disorders, Merck Research Laboratories, Rahway, New Jersey, USA

    Bei B Zhang

  8. Stedman Center for Nutrition and Metabolism Research, Duke University Medical Center, Durham, North Carolina, USA

    Scott A Summers

  9. Department of Cell Biology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Philipp E Scherer

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Contributions

W.L.H. conducted all experiments, except the portions indicated below, and contributed to the writing of the manuscript. R.A.M. conducted in vivo experiments with liver-specific Lkb1−/− mice. Z.V.W. generated all of the ATTAC mouse models used here. K.S. was responsible for the mutagenesis studies of AdipoR1 and AdipoR2. B.M.B. was involved in the studies with INS-1 cells. H.H.B., M.R.W., M.-S.K. and J.T.B. were involved in liquid chromatography–tandem mass spectrometry analysis for determination of sphingolipid content of the samples. K.E.D. assisted in the generation of the Adipor1−/−Adipor2−/− MEFs and high-fat feeding studies using adiponectin transgenic mice. B.T.B. helped in data analysis and RT-PCR of sphingolipid metabolism genes. N.H. performed the experiments with in vivo injections of adiponectin and detection of the protein in beta cells. J.M.R. was involved in designing experiments and protein production. V.M.T. performed ceramidase assays and genotyping. B.B.Z., M.J.B., S.A.S. and P.E.S. were involved in experimental design, data analysis and in the writing of the manuscript.

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Correspondence to Philipp E Scherer.

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Holland, W., Miller, R., Wang, Z. et al. Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Nat Med 17, 55–63 (2011). https://doi.org/10.1038/nm.2277

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