Skip to main content

Advertisement

SpringerLink
Log in

Alpha-synuclein elicits glucose uptake and utilization in adipocytes through the Gab1/PI3K/Akt transduction pathway

  • Research Article
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Insulin is the main glucoregulator that promotes the uptake of glucose by tissues and the subsequent utilization of glucose as an energy source. In this paper, we describe a novel glucoregulator, the alpha-synuclein (SNCA) protein, that has previously been linked to Parkinson’s disease. Treatment with recombinant SNCA promotes glucose uptake in vitro in preadipocytes and in vivo in the adipose tissues and skeletal muscles of mice through the LPAR2/Gab1/PI3K/Akt pathway; these effects occur independently of the insulin receptor. This function of SNCA represents a new mechanistic insight that creates novel avenues of research with respect to the process of glucose regulation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Goedert M (2001) Alpha-synuclein and neurodegenerative diseases. Nat Rev Neurosci 2:492–501

    Article  PubMed  CAS  Google Scholar 

  2. Burre J, Sharma M, Tsetsenis T, Buchman V, Etherton MR, Sudhof TC (2010) Alpha-synuclein promotes SNARE-complex assembly in vivo and in vitro. Science 329:1663–1667

    Article  PubMed  CAS  Google Scholar 

  3. Chandra S, Gallardo G, Fernandez-Chacon R, Schluter OM, Sudhof TC (2005) Alpha-synuclein cooperates with CSPalpha in preventing neurodegeneration. Cell 123:383–396

    Article  PubMed  CAS  Google Scholar 

  4. Duran R, Barrero FJ, Morales B, Luna JD, Ramirez M, Vives F (2010) Plasma alpha-synuclein in patients with Parkinson’s disease with and without treatment. Mov Disord 25:489–493

    Article  PubMed  Google Scholar 

  5. Barbour R, Kling K, Anderson JP, Banducci K, Cole T, Diep L, Fox M, Goldstein JM, Soriano F, Seubert P et al (2008) Red blood cells are the major source of alpha-synuclein in blood. Neurodegener Dis 5:55–59

    Article  PubMed  CAS  Google Scholar 

  6. Park SM, Jung HY, Kim HO, Rhim H, Paik SR, Chung KC, Park JH, Kim J (2002) Evidence that alpha-synuclein functions as a negative regulator of Ca(++)-dependent alpha-granule release from human platelets. Blood 100:2506–2514

    Article  PubMed  CAS  Google Scholar 

  7. Hong S, Lee HK, Kim CY, Seong GJ (2008) Identification and localization of alpha-synuclein in human cornea. Korean J Ophthalmol 22:145–146

    Article  PubMed  Google Scholar 

  8. Kurz A, Rabbani N, Walter M, Bonin M, Thornalley P, Auburger G, Gispert S (2011) Alpha-synuclein deficiency leads to increased glyoxalase I expression and glycation stress. Cell Mol Life Sci 68:721–733

    Article  PubMed  CAS  Google Scholar 

  9. Seo JH, Rah JC, Choi SH, Shin JK, Min K, Kim HS, Park CH, Kim S, Kim EM, Lee SH et al (2002) Alpha-synuclein regulates neuronal survival via Bcl-2 family expression and PI3/Akt kinase pathway. FASEB J 16:1826–1828

    PubMed  CAS  Google Scholar 

  10. Geng X, Lou H, Wang J, Li L, Swanson AL, Sun M, Beers-Stolz D, Watkins S, Perez RG, Drain P (2011) alpha-Synuclein binds the K(ATP) channel at insulin-secretory granules and inhibits insulin secretion. Am J Physiol Endocrinol Metab 300:E276–E286

    Article  PubMed  CAS  Google Scholar 

  11. Hayashi H, Nakagami H, Takami Y, Koriyama H, Mori M, Tamai K, Sun J, Nagao K, Morishita R, Kaneda Y (2009) FHL-2 suppresses VEGF-induced phosphatidylinositol 3-kinase/Akt activation via interaction with sphingosine kinase-1. Arterioscler Thromb Vasc Biol 29:909–914

    Article  PubMed  CAS  Google Scholar 

  12. Abeliovich A, Schmitz Y, Farinas I, Choi-Lundberg D, Ho WH, Castillo PE, Shinsky N, Verdugo JM, Armanini M, Ryan A et al (2000) Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25:239–252

    Article  PubMed  CAS  Google Scholar 

  13. Begriche K, Massart J, Abbey-Toby A, Igoudjil A, Letteron P, Fromenty B (2008) Beta-aminoisobutyric acid prevents diet-induced obesity in mice with partial leptin deficiency. Obesity (Silver Spring) 16:2053–2067

    Article  CAS  Google Scholar 

  14. Shiuchi T, Nakagami H, Iwai M, Takeda Y, Cui T, Chen R, Minokoshi Y, Horiuchi M (2001) Involvement of bradykinin and nitric oxide in leptin-mediated glucose uptake in skeletal muscle. Endocrinology 142:608–612

    Article  PubMed  CAS  Google Scholar 

  15. Shiuchi T, Haque MS, Okamoto S, Inoue T, Kageyama H, Lee S, Toda C, Suzuki A, Bachman ES, Kim YB et al (2009) Hypothalamic orexin stimulates feeding-associated glucose utilization in skeletal muscle via sympathetic nervous system. Cell Metab 10:466–480

    Article  PubMed  CAS  Google Scholar 

  16. Heart E, Choi WS, Sung CK (2000) Glucosamine-induced insulin resistance in 3T3-L1 adipocytes. Am J Physiol Endocrinol Metab 278:E103–E112

    PubMed  CAS  Google Scholar 

  17. Jiang ZY, Zhou QL, Coleman KA, Chouinard M, Boese Q, Czech MP (2003) Insulin signaling through Akt/protein kinase B analyzed by small interfering RNA-mediated gene silencing. Proc Natl Acad Sci USA 100:7569–7574

    Article  PubMed  CAS  Google Scholar 

  18. Taniguchi CM, Emanuelli B, Kahn CR (2006) Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol 7:85–96

    Article  PubMed  CAS  Google Scholar 

  19. Holgado-Madruga M, Emlet DR, Moscatello DK, Godwin AK, Wong AJ (1996) A Grb2-associated docking protein in EGF- and insulin-receptor signalling. Nature 379:560–564

    Article  PubMed  CAS  Google Scholar 

  20. Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF (2003) Met, metastasis, motility and more. Nat Rev Mol Cell Biol 4:915–925

    Article  PubMed  CAS  Google Scholar 

  21. Saltiel AR, Kahn CR (2001) Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414:799–806

    Article  PubMed  CAS  Google Scholar 

  22. Wohrle FU, Daly RJ, Brummer T (2009) Function, regulation and pathological roles of the Gab/DOS docking proteins. Cell Commun Signal 7:22

    Article  PubMed  Google Scholar 

  23. Miinea CP, Sano H, Kane S, Sano E, Fukuda M, Peranen J, Lane WS, Lienhard GE (2005) AS160, the Akt substrate regulating GLUT4 translocation, has a functional Rab GTPase-activating protein domain. Biochem J 391:87–93

    Article  PubMed  CAS  Google Scholar 

  24. Wang Y, Feng W, Xue W, Tan Y, Hein DW, Li XK, Cai L (2009) Inactivation of GSK-3beta by metallothionein prevents diabetes-related changes in cardiac energy metabolism, inflammation, nitrosative damage, and remodeling. Diabetes 58:1391–1402

    Article  PubMed  Google Scholar 

  25. Mariappan MM, Shetty M, Sataranatarajan K, Choudhury GG, Kasinath BS (2008) Glycogen synthase kinase 3beta is a novel regulator of high glucose- and high insulin-induced extracellular matrix protein synthesis in renal proximal tubular epithelial cells. J Biol Chem 283:30566–30575

    Article  PubMed  CAS  Google Scholar 

  26. Eulenfeld R, Schaper F (2009) A new mechanism for the regulation of Gab1 recruitment to the plasma membrane. J Cell Sci 122:55–64

    Article  PubMed  CAS  Google Scholar 

  27. Minokoshi Y, Alquier T, Furukawa N, Kim YB, Lee A, Xue B, Mu J, Foufelle F, Ferre P, Birnbaum MJ et al (2004) AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428:569–574

    Article  PubMed  CAS  Google Scholar 

  28. Rose AJ, Richter EA (2005) Skeletal muscle glucose uptake during exercise: how is it regulated? Physiology (Bethesda) 20:260–270

    Article  CAS  Google Scholar 

  29. Bertrand L, Ginion A, Beauloye C, Hebert AD, Guigas B, Hue L, Vanoverschelde JL (2006) AMPK activation restores the stimulation of glucose uptake in an in vitro model of insulin-resistant cardiomyocytes via the activation of protein kinase B. Am J Physiol Heart Circ Physiol 291:H239–H250

    Article  PubMed  CAS  Google Scholar 

  30. O’Neill HM, Maarbjerg SJ, Crane JD, Jeppesen J, Jorgensen SB, Schertzer JD, Shyroka O, Kiens B, van Denderen BJ, Tarnopolsky MA et al (2011) AMP-activated protein kinase (AMPK) beta1beta2 muscle null mice reveal an essential role for AMPK in maintaining mitochondrial content and glucose uptake during exercise. Proc Natl Acad Sci USA 108:16092–16097

    Article  PubMed  Google Scholar 

  31. Cabin DE, Shimazu K, Murphy D, Cole NB, Gottschalk W, McIlwain KL, Orrison B, Chen A, Ellis CE, Paylor R et al (2002) Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking alpha-synuclein. J Neurosci 22:8797–8807

    PubMed  CAS  Google Scholar 

  32. Hogberg H, Engblom L, Ekdahl A, Lidell V, Walum E, Alberts P (2006) Temperature dependence of O2 consumption; opposite effects of leptin and etomoxir on respiratory quotient in mice. Obesity (Silver Spring) 14:673–682

    Article  CAS  Google Scholar 

  33. Pronin AN, Morris AJ, Surguchov A, Benovic JL (2000) Synucleins are a novel class of substrates for G protein-coupled receptor kinases. J Biol Chem 275:26515–26522

    Article  PubMed  CAS  Google Scholar 

  34. Bisotto S, Fixman ED (2001) Src-family tyrosine kinases, phosphoinositide 3-kinase and Gab1 regulate extracellular signal-regulated kinase 1 activation induced by the type A endothelin-1 G-protein-coupled receptor. Biochem J 360:77–85

    Article  PubMed  CAS  Google Scholar 

  35. Lin SH, Civelli O (2004) Orphan G protein-coupled receptors: targets for new therapeutic interventions. Ann Med 36:204–214

    Article  PubMed  CAS  Google Scholar 

  36. Ohta H, Sato K, Murata N, Damirin A, Malchinkhuu E, Kon J, Kimura T, Tobo M, Yamazaki Y, Watanabe T et al (2003) Ki16425, a subtype-selective antagonist for EDG-family lysophosphatidic acid receptors. Mol Pharmacol 64:994–1005

    Article  PubMed  CAS  Google Scholar 

  37. Haque F, Pandey AP, Cambrea LR, Rochet JC, Hovis JS (2010) Adsorption of alpha-synuclein on lipid bilayers: modulating the structure and stability of protein assemblies. J Phys Chem B 114:4070–4081

    Article  PubMed  CAS  Google Scholar 

  38. Ward Y, Lake R, Yin JJ, Heger CD, Raffeld M, Goldsmith PK, Merino M, Kelly K (2011) LPA receptor heterodimerizes with CD97 to amplify LPA-initiated RHO-dependent signaling and invasion in prostate cancer cells. Cancer Res 71:7301–7311

    Article  PubMed  CAS  Google Scholar 

  39. Choi JW, Herr DR, Noguchi K, Yung YC, Lee CW, Mutoh T, Lin ME, Teo ST, Park KE, Mosley AN et al (2010) LPA receptors: subtypes and biological actions. Annu Rev Pharmacol Toxicol 50:157–186

    Article  PubMed  CAS  Google Scholar 

  40. Kwakkenbos MJ, Kop EN, Stacey M, Matmati M, Gordon S, Lin HH, Hamann J (2004) The EGF-TM7 family: a postgenomic view. Immunogenetics 55:655–666

    Article  PubMed  CAS  Google Scholar 

  41. Vaughan TY, Verma S, Bunting KD (2011) Grb2-associated binding (Gab) proteins in hematopoietic and immune cell biology. Am J Blood Res 1:130–134

    PubMed  CAS  Google Scholar 

  42. Bertola A, Bonnafous S, Cormont M, Anty R, Tanti JF, Tran A, Le Marchand-Brustel Y, Gual P (2007) Hepatocyte growth factor induces glucose uptake in 3T3-L1 adipocytes through A Gab1/phosphatidylinositol 3-kinase/Glut4 pathway. J Biol Chem 282:10325–10332

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This project was supported by the Grant-in-Aid for Scientific Research and the Ministry of Education, Culture, Sports, Science and Technology of the Japanese Government (Monbukagakusho).

Conflict of interest

The authors declare that they have no competing financial interests with respect to this study.

Author information

Authors and Affiliations

  1. Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan

    Gerardo Rodriguez-Araujo, Hironori Nakagami, Hiroki Hayashi, Masaki Mori, Yoichi Takami & Yasufumi Kaneda

  2. Division of Vascular Medicine and Epigenetics, United Graduate School of Child Development, Osaka University, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan

    Hironori Nakagami

  3. Division of Endocrinology and Metabolism, Department of Developmental Physiology, National Institute for Physiological Sciences, Okazaki, Japan

    Tetsuya Shiuchi & Yasuhiko Minokoshi

  4. Department of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan

    Ryuichi Morishita

  5. Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan

    Yoshikazu Nakaoka & Issei Komuro

Authors
  1. Gerardo Rodriguez-Araujo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hironori Nakagami
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hiroki Hayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Masaki Mori
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tetsuya Shiuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yasuhiko Minokoshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yoshikazu Nakaoka
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yoichi Takami
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Issei Komuro
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ryuichi Morishita
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yasufumi Kaneda
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Hironori Nakagami or Yasufumi Kaneda.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 44 kb)

Supplementary material 2 (PDF 3281 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rodriguez-Araujo, G., Nakagami, H., Hayashi, H. et al. Alpha-synuclein elicits glucose uptake and utilization in adipocytes through the Gab1/PI3K/Akt transduction pathway. Cell. Mol. Life Sci. 70, 1123–1133 (2013). https://doi.org/10.1007/s00018-012-1198-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-012-1198-8

Keywords

Search

Navigation