The small molecule indirubin-3'-oxime activates Wnt/β-catenin signaling and inhibits adipocyte differentiation and obesity

International Journal of Obesity

Volumn 38, Issue 8, 2014, Pages 1044-1052

  Choi, O M ^a   Cho, Y H ^a   Choi, S ^a   Lee, S H ^a   Seo, S H ^a   Kim, H Y ^a   Han, G ^a   Min, D S ^a,b   Park, T ^a   Choi, K Y ^a  

^a Yonsei University   (South Korea)

^b Pusan National University   (South Korea)

Author keywords

anti obesity drug; high fat diet; Wnt b catenin pathway; indirubin 3' oxime

Indexed keywords

ANTIOBESITY AGENT; INDIRUBIN-3'-MONOXIME; INDOLE DERIVATIVE; OXIME;

3T3 CELL LINE; ADIPOCYTE; ADIPOGENESIS; ANIMAL; CELL DIFFERENTIATION; CHINESE MEDICINE; DRUG EFFECTS; LIPID DIET; MALE; METABOLIC SYNDROME X; METABOLISM; MOUSE; OBESITY; POLYMERASE CHAIN REACTION; PROCEDURES; WNT SIGNALING PATHWAY;

3T3-L1 CELLS; ADIPOCYTES; ADIPOGENESIS; ANIMALS; ANTI-OBESITY AGENTS; CELL DIFFERENTIATION; DIET, HIGH-FAT; INDOLES; MALE; MEDICINE, CHINESE TRADITIONAL; METABOLIC SYNDROME X; MICE; OBESITY; OXIMES; POLYMERASE CHAIN REACTION; WNT SIGNALING PATHWAY;

EID: 84905659057     PISSN: 03070565     EISSN: 14765497     Source Type: Journal    
DOI: 10.1038/ijo.2013.209     Document Type: Article

References (45)

1. Kopelman P. Obesity as a medical problem. Nature 2000; 404: 635-643. (Pubitemid 30205068)
2. Lobstein T, Baur L, Uauy R. Obesity in children and young people: A crisis in public health. Obes Rev 2004; 5(Suppl 1): S4-S85.
3. Cooke D, Bloom S. The obesity pipeline: Current strategies in the development of anti-obesity drugs. Nat Rev Drug Discov 2006; 5: 919-931. (Pubitemid 44660605)
4. Klonoff DC, Greenway F. Drugs in the pipeline for the obesity market. J Diabetes Sci Technol 2008; 2: 913-918.
5. Prestwich TC, MacDougald OA. Wnt/beta-catenin signaling in adipogenesis and metabolism. Curr Opin Cell Biol 2007; 19: 612-617.
6. Takada I, Kouzmenko AP, Kato S. Wnt and PPARg signaling in osteoblastogenesis and adipogenesis. Nat Rev Rheumatol 2009; 5: 442-447.
7. Ross SE, Hemati N, Longo KA, Bennett CN, Lucas PC, Erickson RL et al. Inhibition of adipogenesis by Wnt Signaling. Science 2000; 289: 950-953. (Pubitemid 30659947)
8. Reya T, Clevers H. Wnt signaling in stem cells and cancer. Nature 2005; 434: 843-850. (Pubitemid 40558990)
9. Komiya Y, Habas R. Wnt signal transduction pathways. Organogenesis 2008; 4: 68-75. (Pubitemid 351881302)
10. Moon RT, Bowerman B, Boutros M, Perrimon N. The promise and perils of Wnt signaling through beta-catenin. Science 2002; 296: 1644-1646. (Pubitemid 34579151)
11. Christodoulides C, Lagathu C, Sethi JK, Vidal-Puig A. Adipogenesis and WNT signalling. Trends Endocrinol Metab 2009; 20: 16-24.
12. Shin EK, Kim JK. Indirubin derivative E804 inhibits angiogenesis. BMC Cancer 2012; 12: 164.
13. Zhang X, Song Y, Wu Y, Dong Y, Lai L, Zhang J et al. Indirubin inhibits tumor growth by antitumor angiogenesis via blocking VEGFR2-mediated JAK/STAT3 signaling in endothelial cell. Int J Cancer 2011; 129: 2502-2511.
14. Hoessel R, Leclerc S, Endicott JA, Nobel ME, Lawrie A, Tunnah P et al. Indirubin, the active constituent of a Chinese antileukaemia medicine, inhibits cyclin-dependent kinases. Nat Cell Biol 1999; 1: 60-67. (Pubitemid 129495012)
15. Marko D, Schatzle S, Friedel A, Genzlinger A, Zankl H, Meijer L et al. Inhibition of cyclin-dependent kinase 1 (CDK1) by indirubin derivatives in human tumour cells. Br J Cancer 2001; 84: 283-289. (Pubitemid 32113458)
16. Polychronopoulos P, Magiatis P, Skaltsounis AL, Myrianthopoulos V, Mikros E, Tarricone A et al. Structural basis for the synthesis of indirubins as potent and selective inhibitors of glycogen synthase kinase-3 and cyclin-dependent kinases. J Med Chem 2004; 47: 935-946. (Pubitemid 38176796)
17. Jeong WJ, Yoon JY, Park JC, Lee SH, Lee SH, Kaduwal S et al. Ras stabilization through aberrant activation of Wnt/b-catenin signaling promotes intestinal tumorigenesis. Sci Signal 2012; 5: R30a.
18. Gould TD, Manji HK. The Wnt signaling pathway in bipolar disorder. Neuroscientist 2002; 8: 497-511.
19. Lee SH, Zahoor M, Hwang JK, Min do S, Choi KY. Valproic acid induces cutaneous wound healing in vivo and enhances keratinocyte motility. PLoS One 2012; 7: E48791.
20. Lee SH, Kim B, Oh MJ, Yoon J, Kim HY, Lee KJ et al. Persicaria hydropiper (L) Spach and its flavonoid components, isoquercitrin and isorhamnetin, activate the Wnt/b-catenin pathway and inhibit adipocyte differentiation of 3T3-L1 cells. Phytother Res 2011; 25: 1629-1635.
21. Sen B, Xie Z, Case N, Ma M, Rubin C, Rubin J. Mechanical strain inhibits adipogenesis in mesenchymal stem cells by stimulating a durable beta-catenin signal. Endocrinology 2008; 149: 6065-6075.
22. ter Haar E, Coll JT, Austen DA, Hsiao HM, Swenson L, Jain J. Structure of GSK3beta reveals a primed phosphorylation mechanism. Nat Struct Biol 2001; 8: 593-596. (Pubitemid 32613006)
23. Després JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature 2006; 444: 881-887. (Pubitemid 46024995)
24. Grundy SM. Does a diagnosis of metabolic syndrome have value in clinical practice? Am J Clin Nutr 2006; 83: 1248-1251. (Pubitemid 44713050)
25. Delarue J, Magnan C. Free fatty acids and insulin resistance. Curr Opin Cin Nutr Metab Care 2007; 10: 142-148. (Pubitemid 46220305)
26. Jensen-Urstad AP, Semenkovich CF. Fatty acid synthase and liver triglyceride metabolism: Housekeeper or messenger? Biochim Biophys Acta 2012; 1821: 747-753.
27. Horton JD, Shimomura I, Ikemoto S, Bashmakov Y, Hammer RE. Overexpression of sterol regulatory element-binding protein-1a in mouse adipose tissue produces adipocyte hypertrophy, increased fatty acid secretion, and fatty liver. J Biol Chem 2003; 278: 36652-36660. (Pubitemid 37139997)
28. Darlington GJ, Wang N, Hanson RW. C/EBP alpha: A critical regulator of genes governing integrative metabolic processes. Curr Opin Genet Dev 1995; 5: 565-570.
29. Lee YH, Sauer B, Johnson PF, Gonzalez FJ. Disruption of the c/ebp alpha gene in adult mouse liver. Mol Cell Biol 1997; 17: 6014-6022. (Pubitemid 27411109)
30. Falcão-Pires I, Castro-Chaves P, Miranda-Silva D, Lourenco AP, Leite-Moreira AF. Physiological, pathological and potential therapeutic roles of adipokines. Drug Discov Today 2012; 17: 880-889.
31. Hiatt WR, Goldfine AB, Kaul S. Cardiovascular risk assessment in the development of new drugs for obesity. JAMA 2012; 308: 1099-1100.
32. Wong D, Sullivan K, Heap G. The pharmaceutical market for obesity therapies. Nat Rev Drug Discov 2012; 1: 669-670.
33. Cristancho AG, Lazar MA. Forming functional fat: A growing understanding of adipocyte differentiation. Nat Rev Mol Cell Biol 2011; 12: 722-734.
34. Ross SE, Erickson RL, Gerin I, DeRose PM, Bajnok L, Longo KA et al. Microarray analyses during adipogenesis: Understanding the effects of Wnt signaling on adipogenesis and the roles of liver X receptor a in adipocyte metabolism. Mol Cell Biol 2002; 22: 5989-5999. (Pubitemid 34815845)
35. Rosen ED, MacDougald OA. Adipocyte differentiation from the inside out. Nat Rev Mol Cell Biol 2006; 7: 885-896. (Pubitemid 44871415)
36. Eisenbrand G, Hippe F, Jakobs S, Muehlbeyer S. Molecular mechanisms of indirubin and its derivatives: Novel anticancer molecules with their origin in traditional Chinese phytomedicine. J Cancer Res Clin Oncol 2004; 130: 627-635. (Pubitemid 39506375)
37. Gan WJ, Yang T, Wen S, Liu Y, Tan Z, Deng C et al. Studies on the mechanism of indirubin action in the treatment of chronic myelocytic leukemia (CML). II. 5-Nucleotidase in the peripheral white blood cells of CML. Chin Acad Med Sci Beijing 1985; 6: 611-613.
38. Grundy SM. What is the contribution of obesity to metabolic syndrome? Endocinol Metab Clin North Am 2004; 33: 267-282. (Pubitemid 38680630)
39. Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, Bales VS et al. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA 2003; 289: 76-79.
40. Shafrir E. Development and consequences of insulin resistance: Lessons from animals with hyperinsulinaemia. Diabetes Metab 1996; 22: 122-131.
41. Fonseca VA. The metabolic syndrome, hyperlipidemia, and insulin resistance. Clin Cornerstone 2005; 7: 61-72. (Pubitemid 43205324)
42. Choi Y, Kim Y, Park S, Lee KW, Park T. Indole-3-carbinol prevents diet-induced obesity through modulation of multiple genes related to adipogenesis, thermogenesis or inflammation in the visceral adipose tissue of mice. J Nutr Biochem 2012; 23: 1732-1739.
43. Hariri N, Thibault L. High-fat diet-induced obesity in animal models. Nutr Res Rev 2010; 23: 270-299.
44. Cheng JH, She H, Han YP, Wang J, Xiong S, Asahina K et al. Wnt antagonism inhibits hepatic stellate cell activation and liver fibrosis. Am J Physiol Gastrointest Liver Physiol 2008; 294: 39-49.
45. Fellmann L, Nascimento AR, Tibirica E, Bousquet P. Murine models for pharmacological studies of the metabolic syndrome. Pharmacol Ther 2013; 137: 331-340. .