AMPK Activators from Natural Products: A Patent Review

  • Uddin, Mohammad Nasir (Korea Bioactive Natural Material Bank, College of Pharmacy, Seoul National University) ;
  • Sharma, Govinda (Korea Bioactive Natural Material Bank, College of Pharmacy, Seoul National University) ;
  • Choi, Hong Seok (BK21 Project Team, College of Pharmacy, Chosun University) ;
  • Lim, Seong-Il (Fermentation and Functionality Research Group, Korea Food Research Institute) ;
  • Oh, Won Keun (Korea Bioactive Natural Material Bank, College of Pharmacy, Seoul National University)
  • Received : 2013.03.08
  • Accepted : 2013.03.13
  • Published : 2013.03.31


AMP-activated protein kinase (AMPK) is a major cellular energy sensor and master regulator of metabolic homeostasis. On activation, this cellular fuel sensing enzyme induces a series of metabolic changes to balance energy consumption via multiple downstream signaling pathways controlling nutrient uptake and energy metabolism. This pivotal role of AMPK has led to the development of numerous AMPK activators which might be used as novel drug candidates in the treatment of AMPK related disorders, diabetes, obesity, and other metabolic diseases. Consequently, a number of patents have been published on AMPK activators from natural products and other sources. This review covers the patented AMPK activators from natural products and their therapeutic potential in treatment or prevention of metabolic diseases including diabetes and obesity.



  1. Ajmo, J.M., Liang, X., Rogers, C.Q., Pennock, B., and You, M., Resveratrol alleviates alcoholic fatty liver in mice. Am J Physiol-Gastr L 295, G833-G842 (2008).
  2. Bateman, A., The structure of a domain common to archaebacteria and the homocystinuria disease protein. Trends Biochem Sci 22, 12-13 (1997).
  3. Bergeron, R., Previs, S.F., Cline, G.W., Perret, P., Russell III, R.R., Young, L.H., and Shulman, G.I., Effect of 5-Aminoimidazole-4-Carboxamide- 1-$\beta$-d-Ribofuranoside Infusion on In Vivo Glucose and Lipid Metabolism in Lean and Obese Zucker Rats. Diabetes 50, 1076-1082 (2001).
  4. Buhl, E.S., Jessen, N., Schmitz, O., Pedersen, S.B., Pedersen, O., Holman, G.D., and Lund, S., Chronic Treatment With 5-Aminoimidazole-4- Carboxamide-1-$\beta$-D-Ribofuranoside Increases Insulin-Stimulated Glucose Uptake and GLUT4 Translocation in Rat Skeletal Muscles in a Fiber Type-Specific Manner. Diabetes 50, 12-17 (2001).
  5. Carling, D., The AMP-activated protein kinase cascade - a unifying system for energy control. Trends Biochem Sci 29, 18-24 (2004).
  6. Cool, B., Zinker, B., Chiou, W., Kifle, L., Cao, N., Perham, M., Dickinson, R., Adler, A., Gagne, G., Iyengar, R., Zhao, G., Marsh, K., Kym, P., Jung, P., Camp, H. S., and Frevert, E., Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cell Metab 3, 403-416 (2006).
  7. Corton, J. M., Gillespie, J. G., Hardie, D. G., Role of the AMP-activated protein kinase in the cellular stress response. Curr Biol 4, 315-324 (1994).
  8. Corton, J.M., Gillespie, J.G., Hawley, S.A., and Hardie, D.G., 5- Aminoimidazole-4-Carboxamide Ribonucleoside. Eur J Biochem 229, 558-565 (1995)
  9. Dagon, Y., Avraham, Y., Berry, E.M., AMPK activation regulates apoptosis, adipogenesis, and lipolysis by eIF2$\alpha$ in adipocytes. Biochem Bioph Res Commu 340, 43-47 (2006).
  10. Derave, W., Ai, H., Ihlemann, J., Witters, L. A., Kristiansen, S., Richter, E.A., and Ploug, T., Dissociation of AMP-activated protein kinase activation and glucose transport in contracting slow-twitch muscle. Diabetes 49, 1281-1287 (2000).
  11. Hardie, D.G., Minireview: The AMP-Activated Protein Kinase Cascade: The Key Sensor of Cellular Energy Status. Endocrinology 144, 5179- 5183 (2003).
  12. Hardie, D.G., AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol 8, 774-785 (2007).
  13. Hardie, D.G., Hawley, S.A., Scott, J.W., AMP-activated protein kinase - development of the energy sensor concept. J Physiol 574, 7-15 (2006).
  14. Henin, N., Vincent, M.F., Gruber, H.E., and den Berghe, G., Inhibition of fatty acid and cholesterol synthesis by stimulation of AMP-activated protein kinase. FASEB J 9, 541-546 (1995).
  15. Holmes, B.F., Kurth-Kraczek, E.J., and Winder, W.W., Chronic activation of 5-AMP-activated protein kinase increases GLUT-4, hexokinase, and glycogen in muscle. J Appl Physiol 87, 1990-1995 (1999).
  16. Hudson, E.R., Pan, D.A., James, J., Lucocq, J.M., Hawley, S.A., Green, K.A., Baba, O., Terashima, T., and Hardie, D.G., A Novel Domain in AMP-Activated Protein Kinase Causes Glycogen Storage Bodies Similar to Those Seen in Hereditary Cardiac Arrhythmias. Curr Biol 13, 861-866 (2003).
  17. Huh, T.L., Song, H., Kim, J.E., Kwon, B.M., Han, D.C., and Kim, H.N., Composition for the treatment of diabetes and metabolic syndrome containing obovatol and its synthesized derivatives. US20100125103 (2010).
  18. Huh, T.L., Song, H., Kim, J.E., Joon, S.Y., and Oh, W.K., Method for preparing Gynostemma pentaphyllum extract with increasing damulin A and damulin B contents, and pharmaceutical compositions of the same for treating metabolic disease. US20110015142 (2011).
  19. Hutchinson, D.S., Summers, R.J., and Bengtsson, T., Regulation of AMPactivated protein kinase activity by G-protein coupled receptors: Potential utility in treatment of diabetes and heart disease. Pharmacol Therapeut 119, 291-310 (2008).
  20. Hwang, J.T., Kwon, D., Park, O., and Kim, M., Resveratrol protects ROSinduced cell death by activating AMPK in H9c2 cardiac muscle cells. Genes Nutr 2, 323-326 (2008).
  21. Kahn, B.B., Alquier, T., Carling, D., and Hardie, D.G., AMP-activated protein kinase: Ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab 1, 15-25 (2005).
  22. Koo, S.H., Flechner, L., Qi, L., Zhang, X., Screaton, R.A., Jeffries, S., Hedrick, S., Xu, W., Boussouar, F., Brindle, P., Takemori, H., and Montminy, M., The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature 437, 1109-1111 (2005).
  23. Lee, J.W., Choe, S.S., Jang, H., Kim, J., Jeong, H.W., Jo, H., Jeong, K.H., Tadi, S., Park, M.G., Kwak, T.H., Man Kim, J., Hyun, D.H., and Kim, J.B., AMPK activation with glabridin ameliorates adiposity and lipid dysregulation in obesity. J. Lipid Res. 53, 1277-1286 (2012).
  24. Lochhead, P. A., Salt, I.P., Walker, K.S., Hardie, D.G., and Sutherland, C., 5-aminoimidazole-4-carboxamide riboside mimics the effects of insulin on the expression of the 2 key gluconeogenic genes PEPCK and glucose-6-phosphatase. Diabetes 49, 896-903 (2000).
  25. López, M., Lelliott, C.J., and Vidal-Puig, A., Hypothalamic fatty acid metabolism: A housekeeping pathway that regulates food intake. Bioessays 29, 248-261 (2007).
  26. Ma, H., Jo, Y.J., Ma, Y., Hong, J.T., Kwon, B.M., and Oh, K.W., Obovatol isolated from Magnolia obovata enhances pentobarbitalinduced sleeping time: Possible involvement of GABAA receptors/ chloride channel activation. Phytomedicine 16, 308-313 (2009).
  27. Merrill, G.F., Kurth, E.J., Hardie, D.G., and Winder, W.W., AICA riboside increases AMP-activated protein kinase, fatty acid oxidation, and glucose uptake in rat muscle. Am J Physiol-Endoc M 273, E1107- E1112 (1997).
  28. Muoio, D.M., Seefeld, K., Witters, L.A., and Coleman, R.A., AMPactivated kinase reciprocally regulates triacylglycerol synthesis and fatty acid oxidation in liver and muscle: evidence that sn-glycerol-3- phosphate acyltransferase is a novel target. Biochem J 338, 783-791 (1999).
  29. Murase, T., AMPK activating agent. US20110118359 (2011a).
  30. Murase, T., AMPK activator. US20110319497 (2011b).
  31. Murase, T., Misawa, K., Haramizu, S., Minegishi, Y., and Hase, T., Nootkatone, a characteristic constituent of grapefruit, stimulates energy metabolism and prevents diet-induced obesity by activating AMPK. Am J Physiol-Endoc M 299, E266-E275 (2010).
  32. Oh, W.K., Nguyen, P.H., Le, T.V.T., Kang, H.W., Shin, E.S., Chio, J.K., Seo, D.B., and Lee, S.J., Composition for preventing or treating obesity related diseases mediated by the activation of AMPK and including 2,5-bis-aryl-3,4-dimethyltetrahydrofuran lignans as active ingredients. US20120083525 (2012).
  33. Park, M.G., and Yoo, S.K., Composition having effect on treatment and prevention of diseases syndrome treatment with glabridin. WO2007058480 (2007).
  34. Polekhina, G., Gupta, A., Michell, B.J., van Denderen, B., Murthy, S., Feil, S.C., Jennings, I.G., Campbell, D.J., Witters, L.A., Parker, M.W., Kemp, B.E., and Stapleton, D., AMPK a Subunit Targets Metabolic Stress Sensing to Glycogen. Curr Biol 13, 867-871 (2003).
  35. Scott, J.W., Hawley, S.A., Green, K.A., Anis, M., Stewart, G., Scullion, G.A., Norman, D.G., and Hardie, D.G., CBS domains form energysensing modules whose binding of adenosine ligands is disrupted by disease mutations. J Clin Invest 113, 274-284 (2004).
  36. Smiley, D. and Umpierrez, G., Metformin/rosiglitazone combination pill ($Avandamet^{(R)}$) for the treatment of patients with Type 2 diabetes. Expert Opin Pharmaco 8, 1353-1364 (2007).
  37. Song, X.M., Fiedler, M., Galuska, D., Ryder, J.W., Fernström, M., Chibalin, A.V., Wallberg-Henriksson, H., and Zierath, J.R., 5- Aminoimidazole-4-carboxamide ribonucleoside treatment improves glucose homeostasis in insulin-resistant diabetic (ob/ob) mice. Diabetologia 45, 56-65 (2002).
  38. Sullivan, J.E., Brocklehurst, K.J., Marley, A.E., Carey, F., Carling, D., and Beri, R.K., Inhibition of lipolysis and lipogenesis in isolated rat adipocytes with AICAR, a cell-permeable activator of AMP-activated protein kinase. FEBS Lett 353, 33-36 (1994).
  39. Szkudelska, K. and Szkudelski, T., Resveratrol, obesity and diabetes. Eur J Pharmacol 635, 1-8 (2010).
  40. Trevisan, M., Liu, J., Bahsas, F.B., and Menotti, A., Syndrome X and Mortality: A Population-based Study. Am J Epidemiol 148, 958-966 (1998).
  41. Winder, W.W., Holmes, B.F., Rubink, D.S., Jensen, E.B., Chen, M., and Holloszy, J.O., Activation of AMP-activated protein kinase increases mitochondrial enzymes in skeletal muscle. J Appl Physiol 88, 2219- 2226 (2000).
  42. Woods, A., Azzout-Marniche, D., Foretz, M., Stein, S.C., Lemarchand, P., Ferré, P., Foufelle, F., and Carling, D., Characterization of the Role of AMP-Activated Protein Kinase in the Regulation of Glucose- Activated Gene Expression Using Constitutively Active and Dominant Negative Forms of the Kinase. Mol Cell Biol 20, 6704-6711 (2000).
  43. Wright, D.C., Geiger, P.C., Holloszy, J.O., and Han, D.H., Contractionand hypoxia-stimulated glucose transport is mediated by a Ca2+- dependent mechanism in slow-twitch rat soleus muscle. Am J Physiol- Endoc M 288, E1062-E1066 (2005).
  44. Ye, Y., James, D.E., Tan, M., Cooney, G.J., Ke, C., Kraegen, E.W., Chen, T., Ye, J., and Li, X., Use of compounds extracetd from Momordica charantia L. in the manufacture of medicaments for prevention and treatment of diabetes and obesity. EP2255816 (2010).
  45. Zong, H., Ren, J.M., Young, L.H., Pypaert, M., Mu, J., Birnbaum, M.J., and Shulman, G.I., AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proc Natl Acad Sci 99, 15983-15987 (2002).