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Molecular Medicine

, Volume 17, Issue 9–10, pp 1022–1030 | Cite as

Small-Molecule Activators of AMP-Activated Protein Kinase (AMPK), RSVA314 and RSVA405, Inhibit Adipogenesis

  • Valérie Vingtdeux
  • Pallavi Chandakkar
  • Haitian Zhao
  • Peter Davies
  • Philippe Marambaud
Research Article

Abstract

AMP-activated protein kinase (AMPK) is a sensor and regulator of cellular energy metabolism potentially Implicated In a broad range of conditions, including obesity and Alzheimer’s disease. Its role in the control of key metabolic enzymes makes this kinase a central player in glucose and lipid homeostasis. Recently, by screening a library of synthetic small molecules selected for their structural similarity with the natural polyphenol resveratrol, we identified RSVA314 and RSVA405 as potent indirect activators of AMPK (half-maximal effective concentration (EC50) = 1 µmol/L in cell-based assays). Here we show that RSVA314 and RSVA405 can significantly activate AMPK and inhibit acetyl-CoA carboxylase (ACC), one target of AMPK and a key regulator of fatty acid biogenesis, in nondifferentiated and proliferating 3T3-L1 adipocytes. We found that RSVA314 and RSVA405 treatments inhibited 3T3-L1 adipocyte differentiation by interfering with mitotic clonal expansion during preadipocyte proliferation (halfmaximal inhibitory concentration (IC50) = 0.5 µmol/L). RSVA314 and RSVA405 prevented the adipogenesis-dependent transcriptional changes of multiple gene products involved in the adipogenic process, including peroxisome proliferator-activated receptor (PPAR)-γ, CCAAT/enhancer-binding protein α (C/EBPα), fatty acid synthase, fatty acid binding protein 4 (aP2), RANTES or resistin. Furthermore, orally administered RSVA405 at 20 and 100 mg/kg/d significantly reduced the body weight gain of mice fed a high-fat diet. This work shows that the novel small-molecule activators of AMPK (RSVA314 and RSVA405) are potent inhibitors of adipogenesis and thus may have therapeutic potential against obesity.

Notes

Acknowledgments

This work was supported in part by the National Institutes of Health (grant PO1 AT004511; National Center for Complementary and Alternative Medicine [NCCAM] Project 2 to P Marambaud).

References

  1. 1.
    Hardie DG. (2007) AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat. Rev. Mol. Cell Biol. 8:774–85.CrossRefPubMedGoogle Scholar
  2. 2.
    Fogarty S, et al. (2010) Calmodulin-dependent protein kinase kinase-beta activates AMPK without forming a stable complex: synergistic effects of Ca2+ and AMP. Biochem. J. 426:109–18.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Carling D, Sanders MJ, Woods A. (2008) The regulation of AMP-activated protein kinase by upstream kinases. Int. J. Obes. (Lond). 32 Suppl 4: S55–9.CrossRefGoogle Scholar
  4. 4.
    Viollet B, et al. (2009) Targeting the AMPK pathway for the treatment of type 2 diabetes. Front. Biosci. 14:3380–400.CrossRefGoogle Scholar
  5. 5.
    Zhang BB, Zhou G, Li C. (2009) AMPK: an emerging drug target for diabetes and the metabolic syndrome. Cell. Metab. 9:407–16.CrossRefPubMedGoogle Scholar
  6. 6.
    Spiegelman BM, Flier JS. (2001) Obesity and the regulation of energy balance. Cell. 104:531–43.CrossRefPubMedGoogle Scholar
  7. 7.
    Farmer SR. (2006) Transcriptional control of adipocyte formation. Cell. Metab. 4:263–73.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Rosen ED, Spiegelman BM. (2000) Molecular regulation of adipogenesis. Annu. Rev. Cell Dev. Biol. 16:145–71.CrossRefPubMedGoogle Scholar
  9. 9.
    Ahn J, Lee H, Kim S, Park J, Ha T. (2008) The anti-obesity effect of quercetin is mediated by the AMPK and MAPK signaling pathways. Biochem. Biophys. Res. Commun. 373:545–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Giri S, et al. (2006) AICAR inhibits adipocyte differentiation in 3T3L1 and restores metabolic alterations in diet-induced obesity mice model. Nutr. Metab. (Lond). 3:31.CrossRefGoogle Scholar
  11. 11.
    Hwang JT, et al. (2007) Anti-obesity effects of ginsenoside Rh2 are associated with the activation of AMPK signaling pathway in 3T3-L1 adipocyte. Biochem. Biophys. Res. Commun. 364:1002–8.CrossRefPubMedGoogle Scholar
  12. 12.
    Zhou Y, et al. (2009) Inhibitory effects of A-769662, a novel activator of AMP-activated protein kinase, on 3T3-L1 adipogenesis. Biol. Pharm. Bull. 32:993–8.CrossRefPubMedGoogle Scholar
  13. 13.
    Vingtdeux V, et al. (2010) AMP-activated protein kinase signaling activation by resveratrol modulates amyloid-beta peptide metabolism. J. Biol. Chem. 285:9100–13.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Hawley SA, et al. (2010) Use of cells expressing gamma subunit variants to identify diverse mechanisms of AMPK activation. Cell. Metab. 11:554–65.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Canto C, Auwerx J. (2009) PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Curr. Opin. Lipidol. 20:98–105.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Um JH, et al. (2010) AMPK-deficient mice are resistant to the metabolic effects of resveratrol. Diabetes. 59:554–63.CrossRefPubMedGoogle Scholar
  17. 17.
    Baile CA, et al. (2011) Effect of resveratrol on fat mobilization. Ann. N. Y. Acad. Sci. 1215:40–7.CrossRefPubMedGoogle Scholar
  18. 18.
    Marambaud P, Zhao H, Davies P. (2005) Resveratrol promotes clearance of Alzheimer’s disease amyloid-beta peptides. J. Biol. Chem. 280:37377–82.CrossRefPubMedGoogle Scholar
  19. 19.
    Vingtdeux V, Dreses-Werringloer U, Zhao H, Davies P, Marambaud P. (2008) Therapeutic potential of resveratrol in Alzheimer’s disease. BMC Neurosci. 9 Suppl 2:S6.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Vingtdeux V, et al. (2011) Novel synthetic small-molecule activators of AMPK as enhancers of autophagy and amyloid-beta peptide degradation. FASEB J. 25:219–31.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Baur JA, et al. (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 444:337–42.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Rayalam S, Yang JY, Ambati S, Della-Fera MA, Baile CA. (2008) Resveratrol induces apoptosis and inhibits adipogenesis in 3T3-L1 adipocytes. Phytother. Res. 22:1367–71.CrossRefPubMedGoogle Scholar
  23. 23.
    Fujii N, Jessen N, Goodyear LJ. (2006) AMP-activated protein kinase and the regulation of glucose transport. Am. J. Physiol. Endocrinol. Metab. 291:E867–77.CrossRefPubMedGoogle Scholar
  24. 24.
    Lagouge M, et al. (2006) Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell. 127:1109–22.CrossRefPubMedGoogle Scholar
  25. 25.
    Fogarty S, Hardie DG. (2010) Development of protein kinase activators: AMPK as a target in metabolic disorders and cancer. Biochim. Biophys. Acta. 1804:581–91.CrossRefPubMedGoogle Scholar
  26. 26.
    Viollet B, et al. (2010) AMPK inhibition in health and disease. Crit. Rev. Biochem. Mol. Biol. 45:276–95.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Musi N, Goodyear LJ. (2002) Targeting the AMP-activated protein kinase for the treatment of type 2 diabetes. Curr. Drug Targets Immune Endocr. Metabol. Disord. 2:119–27.CrossRefPubMedGoogle Scholar
  28. 28.
    Villena JA, et al. (2004) Induced adiposity and adipocyte hypertrophy in mice lacking the AMP-activated protein kinase-alpha2 subunit. Diabetes. 53:2242–9.CrossRefPubMedGoogle Scholar
  29. 29.
    Daval M, et al. (2005) Anti-lipolytic action of AMP-activated protein kinase in rodent adipocytes. J. Biol. Chem. 280:25250–7.CrossRefPubMedGoogle Scholar
  30. 30.
    Corton JM, Gillespie JG, Hawley SA, Hardie DG. (1995) 5-aminoimidazole-4-carboxamide ribonucleoside: a specific method for activating AMP-activated protein kinase in intact cells? Eur. J. Biochem. 229:558–65.CrossRefPubMedGoogle Scholar
  31. 31.
    Wullschleger S, Loewith R, Hall MN. (2006) TOR signaling in growth and metabolism. Cell. 124:471–84.CrossRefGoogle Scholar
  32. 32.
    Chan EY. (2009) mTORC1 phosphorylates the ULK1-mAtg13-FIP200 autophagy regulatory complex. Sci. Signal. 2:pe51.CrossRefPubMedGoogle Scholar
  33. 33.
    Kim J, Kundu M, Viollet B, Guan KL. (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol. 13:132–41.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Egan DF, et al. (2011) Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science. 331:456–61.CrossRefPubMedGoogle Scholar
  35. 35.
    Maiuri MC, Zalckvar E, Kimchi A, Kroemer G. (2007) Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat. Rev. Mol. Cell Biol. 8:741–52.CrossRefPubMedGoogle Scholar
  36. 36.
    Narkar VA, et al. (2008) AMPK and PPARdelta agonists are exercise mimetics. Cell. 134:405–15.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© The Feinstein Institute for Medical Research 2011
www.feinsteininstitute.org

Authors and Affiliations

  • Valérie Vingtdeux
    • 1
  • Pallavi Chandakkar
    • 1
  • Haitian Zhao
    • 1
  • Peter Davies
    • 1
    • 2
  • Philippe Marambaud
    • 1
    • 2
  1. 1.Litwin-Zucker Research Center for the Study of Alzheimer’s DiseaseThe Feinstein Institute for Medical ResearchManhassetUSA
  2. 2.Department of PathologyAlbert Einstein College of MedicineBronxUSA

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