Berberine, a Natural Plant Product, Activates AMP-Activated Protein Kinase With Beneficial Metabolic Effects in Diabetic and Insulin-Resistant States

Diabetes - Tập 55 Số 8 - Trang 2256-2264 - 2006
Yun Sok Lee1,2, Woo S. Kim1,2, Kang H. Kim1,2, Myung Ja Yoon1, Hye J. Cho1, Yun Shen3,4, Ji‐Ming Ye3, Chul H. Lee5, Won Keun Oh5, Chul T. Kim5, Cordula Hohnen-Behrens3, Alison K. Gosby3, Edward W. Kraegen3, David E. James3, Jae Bum Kim1,2
1Department of Biological Sciences, Seoul National University, Seoul, Korea
2Research Center for Cellulomics, Seoul, Korea
3Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia
4Shanghai Institute of Biological Sciences, Chinese Academy of Sciences, Shanghai, China
5Korea Research Institute of Bioscience and Biotechnology, Taejon, Korea

Tóm tắt

Berberine has been shown to have antidiabetic properties, although its mode of action is not known. Here, we have investigated the metabolic effects of berberine in two animal models of insulin resistance and in insulin-responsive cell lines. Berberine reduced body weight and caused a significant improvement in glucose tolerance without altering food intake in db/db mice. Similarly, berberine reduced body weight and plasma triglycerides and improved insulin action in high-fat–fed Wistar rats. Berberine downregulated the expression of genes involved in lipogenesis and upregulated those involved in energy expenditure in adipose tissue and muscle. Berberine treatment resulted in increased AMP-activated protein kinase (AMPK) activity in 3T3-L1 adipocytes and L6 myotubes, increased GLUT4 translocation in L6 cells in a phosphatidylinositol 3′ kinase–independent manner, and reduced lipid accumulation in 3T3-L1 adipocytes. These findings suggest that berberine displays beneficial effects in the treatment of diabetes and obesity at least in part via stimulation of AMPK activity.

Từ khóa


Tài liệu tham khảo

Kopelman PG: Obesity as a medical problem. Nature 404:635–643,2000

Spiegelman BM, Flier JS: Obesity and the regulation of energy balance. Cell 104:531–543,2001

Sewter C, Vidal-Puig A: PPARgamma and the thiazolidinediones: molecular basis for a treatment of ‘Syndrome X’?Diabetes Obes Metab 4:239–248,2002

Leverve XM, Guigas B, Detaille D, Batandier C, Koceir EA, Chauvin C, Fontaine E, Wiernsperger NF: Mitochondrial metabolism and type-2 diabetes: a specific target of metformin. Diabetes Metab 29:6S88–6S94,2003

Fryer LG, Parbu-Patel A, Carling D: The anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways. J Biol Chem 277:25226–25232,2002

Riddle MC: Oral pharmacologic management of type 2 diabetes. Am Fam Physician 60:2613–2620,1999

Nawrocki AR, Rajala MW, Tomas E, Pajvani UB, Saha AK, Trumbauer ME, Pang Z, Chen AS, Ruderman NB, Chen H, Rossetti L, Scherer PE: Mice lacking adiponectin show decreased hepatic insulin sensitivity and reduced responsiveness to PPARgamma-agonists. J Biol Chem 281:2654–2660,2006

Hawley SA, Gadalla AE, Olsen GS, Hardie DG: The antidiabetic drug metformin activates the AMP-activated protein kinase cascade via an adenine nucleotide-independent mechanism. Diabetes 51:2420–2425,2002

Marles RJ, Farnsworth NR: Antidiabetic plants and their active constituents. Phytomedicine 2:137–189,1995

Wang HX, Ng TB: Natural products with hypoglycemic, hypotensive, hypocholesterolemic, antiatherosclerotic and antithrombotic activities. Life Sci 65:2663–2677,1999

Ni YX: [Therapeutic effect of berberine on 60 patients with type II diabetes mellitus and experimental research]. Zhong Xi Yi Jie He Za Zhi 8:711–713,1988 [article in Chinese]

Yin J, Hu R, Chen M, Tang J, Li F, Yang Y, Chen J: Effects of berberine on glucose metabolism in vitro. Metabolism 51:1439–1443,2002

Leng SH, Lu FE, Xu LJ: Therapeutic effects of berberine in impaired glucose tolerance rats and its influence on insulin secretion. Acta Pharmacol Sin 25:496–502,2004

Ko BS, Choi SB, Park SK, Jang JS, Kim YE, Park S: Insulin sensitizing and insulinotropic action of berberine from Cortidis rhizoma. Biol Pharm Bull 28:1431–1437,2005

Ye JM, Iglesias MA, Watson DG, Ellis B, Wood L, Jensen PB, Sorensen RV, Larsen PJ, Cooney GJ, Wassermann K, Kraegen EW: PPARalpha /gamma ragaglitazar eliminates fatty liver and enhances insulin action in fat-fed rats in the absence of hepatomegaly. Am J Physiol Endocrinol Metab 284:E531–E540,2003

Ye JM, Doyle PJ, Iglesias MA, Watson DG, Cooney GJ, Kraegen EW: Peroxisome proliferator–activated receptor (PPAR)-α activation lowers muscle lipids and improves insulin sensitivity in high fat-fed rats: comparison with PPAR-γ activation. Diabetes 50:411–417,2001

Kim JB, Spiegelman BM: ADD1/SREBP1 promotes adipocyte differentiation and gene expression linked to fatty acid metabolism. Genes Dev 10:1096–1107,1996

Shewan AM, Marsh BJ, Melvin DR, Martin S, Gould GW, James DE: The cytosolic C-terminus of the glucose transporter GLUT4 contains an acidic cluster endosomal targeting motif distal to the dileucine signal. Biochem J 350:99–107,2000

Govers R, Coster AC, James DE: Insulin increases cell surface GLUT4 levels by dose dependently discharging GLUT4 into a cell surface recycling pathway. Mol Cell Biol 24:6456–6466,2004

Lee YS, Lee HH, Park J, Yoo EJ, Glackin CA, Choi YI, Jeon SH, Seong RH, Park SD, Kim JB: Twist2, a novel ADD1/SREBP1c interacting protein, represses the transcriptional activity of ADD1/SREBP1c. Nucleic Acid Res 31:7165–7174,2003

Carling D: AMP-activated protein kinase: balancing the scales. Biochimie 87:87–91,2005

Davies SP, Sim AT, Hardie DG: Location and function of three sites phosphorylated on rat acetyl-CoA carboxylase by the AMP-activated protein kinase. Eur J Biochem 187:183–190,1990

Carling D, Clarke PR, Zammit VA, Hardie DG: Purification and characterization of the AMP-activated protein kinase: copurification of acetyl-CoA carboxylase kinase and 3-hydroxy-3-methylglutaryl-CoA reductase kinase activities. Eur J Biochem 186:129–136,1989

Carling D, Zammit VA, Hardie DG: A common bicyclic protein kinase cascade inactivates the regulatory enzymes of fatty acid and cholesterol biosynthesis. FEBS Lett 223:217–222,1987

Kurth-Kraczek EJ, Hirshman MF, Goodyear LJ, Winder WW: 5′ AMP-activated protein kinase activation causes GLUT4 translocation in skeletal muscle. Diabetes 48:1667–1671,1999

Frevert EU, Kahn BB: Differential effects of constitutively active phosphatidylinositol 3-kinase on glucose transport, glycogen synthase activity, and DNA synthesis in 3T3–L1 adipocytes. Mol Cell Biol 17:190–198,1997

Russell RR 3rd, Bergeron R, Shulman GI, Young LH: Translocation of myocardial GLUT-4 and increased glucose uptake through activation of AMPK by AICAR. Am J Physiol 277:H643–H649,1999

Zang M, Zuccollo A, Hou X, Nagata D, Walsh K, Herscovitz H, Brecher P, Ruderman NB, Cohen RA: AMP-activated protein kinase is required for the lipid-lowering effect of metformin in insulin-resistant human HepG2 cells. J Biol Chem 279:47898–47905,2004

Hu E, Kim JB, Sarraf P, Spiegelman BM: Inhibition of adipogenesis through MAP kinase-mediated phosphorylation of PPARgamma. Science 274:2100–2103,1996

Diradourian C, Girard J, Pegorier JP: Phosphorylation of PPARs: from molecular characterization to physiological relevance. Biochimie 87:33–38,2005

Camp HS, Tafuri SR, Leff T: c-Jun N-terminal kinase phosphorylates peroxisome proliferator-activated receptor-gamma1 and negatively regulates its transcriptional activity. Endocrinology 140:392–397,1999

Leff T: AMP-activated protein kinase regulates gene expression by direct phosphorylation of nuclear proteins. Biochem Soc Trans 31:224–227,2003

Adams M, Reginato MJ, Shao D, Lazar MA, Chatterjee VK: Transcriptional activation by peroxisome proliferator-activated receptor gamma is inhibited by phosphorylation at a consensus mitogen-activated protein kinase site. J Biol Chem 272:5128–5132,1997

Zhang B, Berger J, Zhou G, Elbrecht A, Biswas S, White-Carrington S, Szalkowski D, Moller DE: Insulin- and mitogen-activated protein kinase-mediated phosphorylation and activation of peroxisome proliferator-activated receptor gamma. J Biol Chem 271:31771–31774,1996

Wright HM, Clish CB, Mikami T, Hauser S, Yanagi K, Hiramatsu R, Serhan CN, Spiegelman BM: A synthetic antagonist for the peroxisome proliferator-activated receptor gamma inhibits adipocyte differentiation. J Biol Chem 275:1873–1877,2000

Taylor CE, Greenough WB 3rd: Control of diarrheal diseases. Annu Rev Public Health 10:221–244,1989

Jantova S, Cipak L, Cernakova M, Kost’alova D: Effect of berberine on proliferation, cell cycle and apoptosis in HeLa and L1210 cells. J Pharm Pharmacol 55:1143–1149,2003

Anis KV, Rajeshkumar NV, Kuttan R: Inhibition of chemical carcinogenesis by berberine in rats and mice. J Pharm Pharmacol 53:763–768,2001

Amin AH, Subbaiah TV, Abbasi KM: Berberine sulfate: antimicrobial activity, bioassay, and mode of action. Can J Microbiol 15:1067–1076,1969

Chen QM, Xie MZ: [Studies on the hypoglycemic effect of Coptis chinensis and berberine]. Yao Xue Xue Bao 21:401–406,1986 [article in Chinese]

Zhou LB, Chen MD, Wang X, Song HD, Yang Y, Tang JF, Li FY, Xu MY, Chen JL: [Effect of berberine on the differentiation of adipocyte]. Zhonghua Yi Xue Za Zhi 83:338–340,2003 [article in Chinese]

Kong W, Wei J, Abidi P, Lin M, Inaba S, Li C, Wang Y, Wang Z, Si S, Pan H, Wang S, Wu J, Li Z, Liu J, Jiang JD: Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med 10:1344–1351,2004

Rosen ED, Spiegelman BM: Molecular regulation of adipogenesis. Annu Rev Cell Dev Biol 16:145–171,2000

Rosen ED, Walkey CJ, Puigserver P, Spiegelman BM: Transcriptional regulation of adipogenesis. Genes Dev 14:1293–1307,2000

Xi X, Han J, Zhang JZ: Stimulation of glucose transport by AMP-activated protein kinase via activation of p38 mitogen-activated protein kinase. J Biol Chem 276:41029–41034,2001

Fleury C, Neverova M, Collins S, Raimbault S, Champigny O, Levi-Meyrueis C, Bouillaud F, Seldin MF, Surwit RS, Ricquier D, Warden CH: Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Nat Genet 15:269–272,1997

Flier JS, Lowell BB: Obesity research springs a proton leak. Nat Genet 15:223–224,1997

Fryer LG, Carling D: AMP-activated protein kinase and the metabolic syndrome. Biochem Soc Trans 33:362–366,2005

Kahn BB, Alquier T, Carling D, Hardie DG: AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab 1:15–25,2005

Saenz A, Fernandez-Esteban I, Mataix A, Ausejo M, Roque M, Moher D: Metformin monotherapy for type 2 diabetes mellitus (Review). Cochrane Database Syst Rev 20:CD002966,2005

Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE: Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108:1167–1174,2001

Huypens P, Quartier E, Pipeleers D, Van de Casteele M: Metformin reduces adiponectin protein expression and release in 3T3–L1 adipocytes involving activation of AMP activated protein kinase. Eur J Pharmacol 518:90–95,2005

Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA: An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem 270:12953–12956,1995

Ye JM, Dzamko N, Cleasby ME, Hegarty BD, Furler SM, Cooney GJ, Kraegen EW: Direct demonstration of lipid sequestration as a mechanism by which rosiglitazone prevents fatty-acid-induced insulin resistance in the rat: comparison with metformin. Diabetologia 47:1306–1313,2004