The involvement of the wnt signaling pathway and TCF7L2 in diabetes mellitus: The current understanding, dispute, and perspective

Cell & Bioscience

Tianru Jin¹  Yu-ting Alex Chiang¹  Wilfred Ip¹ 

[1] Toronto General Research Institute, University Health Network, 101 College Street, Toronto, ON, M5G 1L7, Canada

关键词: TCF7L2;    Insulin;    Stress;    FOXO;    β-cat/TCF;    β-catenin;    Wnt;   

Others  :  793258
DOI  :  10.1186/2045-3701-2-28

 received in 2012-05-08, accepted in 2012-06-19,  发布年份 2012

【 摘 要 】

The Wnt signaling pathway was initially discovered for its role in tumorigenesis and the development of Drosophila and other eukaryotic organisms. The key effector of this pathway, the bipartite transcription factor β-cat/TCF, is formed by free β-catenin (β-cat) and a TCF protein, including TCF7L2. Extensive recent investigations have highlighted the role of the Wnt signaling pathway in metabolic homeostasis and its implication in diabetes and other metabolic diseases. Genome-wide association studies have shown that several key components of the Wnt signaling pathway are implicated in metabolic homeostasis and the development of type 2 diabetes (T2D). Despite controversial observations regarding the role of Wnt signaling in the development and function of pancreatic islets, the discovery of the association between certain single nucleotide polymorphisms of TCF7L2 and T2D susceptibility has fueled great efforts to explore the role of Wnt signaling in the function of pancreatic β-cells and glucose homeostasis. Here we have introduced our basic understanding of the canonical Wnt signaling pathway, summarized our current knowledge on its implication in metabolic homeostasis and T2D, discussed the work on TCF7L2 as a T2D susceptibility gene, and presented the controversial role of Wnt signaling and TCF7L2 in pancreatic islets as well as their potential metabolic function in other organs. We then expanded our view into the crosstalk among Wnt, insulin and FOXO signaling cascades, which further illustrates the complexity of the Wnt signaling pathway in metabolic homeostasis. Finally, we have presented our perspectives.

【 授权许可】

   
2012 Ip et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]Moon RT, Brown JD, Torres M: WNTs modulate cell fate and behavior during vertebrate development. Trends Genet 1997, 13:157-162.
• [2]Peifer M, Polakis P: Wnt signaling in oncogenesis and embryogenesis–a look outside the nucleus. Science 2000, 287:1606-1609.
• [3]Nusse R, Varmus HE: Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. Cell 1982, 31:99-109.
• [4]Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, Kinzler KW: Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science 1997, 275:1787-1790.
• [5]Yi F, Brubaker PL, Jin T: TCF-4 mediates cell type-specific regulation of proglucagon gene expression by beta-catenin and glycogen synthase kinase-3beta. J Biol Chem 2005, 280:1457-1464.
• [6]Jin T, Liu L: The Wnt signaling pathway effector TCF7L2 and type 2 diabetes mellitus. Mol Endocrinol 2008, 22:2383-2392.
• [7]Clevers H: Wnt/beta-catenin signaling in development and disease. Cell 2006, 127:469-480.
• [8]Rachner TD, Khosla S, Hofbauer LC: Osteoporosis: now and the future. Lancet 2011, 377:1276-1287.
• [9]Naito AT, Shiojima I, Komuro I: Wnt signaling and aging-related heart disorders. Circ Res 2010, 107:1295-1303.
• [10]MacDonald BT, Tamai K, He X: Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell 2009, 17:9-26.
• [11]Yang Y: Wnt signaling in development and disease. Cell Biosci 2012, 2:14. BioMed Central Full Text
• [12]Korinek V, Barker N, Moerer P, van Donselaar E, Huls G, Peters PJ, Clevers H: Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat Genet 1998, 19:379-383.
• [13]Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J, Helgason A, Stefansson H, Emilsson V, Helgadottir A, et al.: Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet 2006, 38:320-323.
• [14]Schafer SA, Tschritter O, Machicao F, Thamer C, Stefan N, Gallwitz B, Holst JJ, Dekker JM, t Hart LM, Nijpels G, et al.: Impaired glucagon-like peptide-1-induced insulin secretion in carriers of transcription factor 7-like 2 (TCF7L2) gene polymorphisms. Diabetologia 2007, 50:2443-2450.
• [15]Saxena R, Gianniny L, Burtt NP, Lyssenko V, Giuducci C, Sjogren M, Florez JC, Almgren P, Isomaa B, Orho-Melander M, et al.: Common single nucleotide polymorphisms in TCF7L2 are reproducibly associated with type 2 diabetes and reduce the insulin response to glucose in nondiabetic individuals. Diabetes 2006, 55:2890-2895.
• [16]Prokunina-Olsson L, Kaplan LM, Schadt EE, Collins FS: Alternative splicing of TCF7L2 gene in omental and subcutaneous adipose tissue and risk of type 2 diabetes. PLoS One 2009, 4:e7231.
• [17]Shu L, Matveyenko AV, Kerr-Conte J, Cho JH, McIntosh CH, Maedler K: Decreased TCF7L2 protein levels in type 2 diabetes mellitus correlate with downregulation of GIP- and GLP-1 receptors and impaired beta-cell function. Hum Mol Genet 2009, 18:2388-2399.
• [18]Shu L, Sauter NS, Schulthess FT, Matveyenko AV, Oberholzer J, Maedler K: Transcription factor 7-like 2 regulates beta-cell survival and function in human pancreatic islets. Diabetes 2008, 57:645-653.
• [19]Groves CJ, Zeggini E, Minton J, Frayling TM, Weedon MN, Rayner NW, Hitman GA, Walker M, Wiltshire S, Hattersley AT, McCarthy MI: Association analysis of 6,736 U.K. subjects provides replication and confirms TCF7L2 as a type 2 diabetes susceptibility gene with a substantial effect on individual risk. Diabetes 2006, 55:2640-2644.
• [20]Guo T, Hanson RL, Traurig M, Muller YL, Ma L, Mack J, Kobes S, Knowler WC, Bogardus C, Baier LJ: TCF7L2 is not a major susceptibility gene for type 2 diabetes in Pima Indians: analysis of 3,501 individuals. Diabetes 2007, 56:3082-3088.
• [21]Grant SF, Hakonarson H, Schwartz S: Can the genetics of type 1 and type 2 diabetes shed light on the genetics of latent autoimmune diabetes in adults? Endocr Rev 2010, 31:183-193.
• [22]Lyssenko V, Jonsson A, Almgren P, Pulizzi N, Isomaa B, Tuomi T, Berglund G, Altshuler D, Nilsson P, Groop L: Clinical risk factors, DNA variants, and the development of type 2 diabetes. N Engl J Med 2008, 359:2220-2232.
• [23]Lyssenko V, Lupi R, Marchetti P, Del Guerra S, Orho-Melander M, Almgren P, Sjogren M, Ling C, Eriksson KF, Lethagen AL, et al.: Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes. J Clin Invest 2007, 117:2155-2163.
• [24]Jin T: The WNT signalling pathway and diabetes mellitus. Diabetologia 2008, 51:1771-1780.
• [25]Manolagas SC, Almeida M: Gone with the Wnts: beta-catenin, T-cell factor, forkhead box O, and oxidative stress in age-dependent diseases of bone, lipid, and glucose metabolism. Mol Endocrinol 2007, 21:2605-2614.
• [26]Almeida M, Han L, Martin-Millan M, O'Brien CA, Manolagas SC: Oxidative stress antagonizes Wnt signaling in osteoblast precursors by diverting beta-catenin from T cell factor- to forkhead box O-mediated transcription. J Biol Chem 2007, 282:27298-27305.
• [27]Jin T, George Fantus I, Sun J: Wnt and beyond Wnt: multiple mechanisms control the transcriptional property of beta-catenin. Cell Signal 2008, 20:1697-1704.
• [28]Rijsewijk F, Schuermann M, Wagenaar E, Parren P, Weigel D, Nusse R: The Drosophila homolog of the mouse mammary oncogene int-1 is identical to the segment polarity gene wingless. Cell 1987, 50:649-657.
• [29]Zeng X, Tamai K, Doble B, Li S, Huang H, Habas R, Okamura H, Woodgett J, He X: A dual-kinase mechanism for Wnt co-receptor phosphorylation and activation. Nature 2005, 438:873-877.
• [30]Dierick H, Bejsovec A: Cellular mechanisms of wingless/Wnt signal transduction. Curr Top Dev Biol 1999, 43:153-190.
• [31]Stambolic V, Ruel L, Woodgett JR: Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells. Current biology : CB 1996, 6:1664-1668.
• [32]Hino S, Tanji C, Nakayama KI, Kikuchi A: Phosphorylation of beta-catenin by cyclic AMP-dependent protein kinase stabilizes beta-catenin through inhibition of its ubiquitination. Mol Cell Biol 2005, 25:9063-9072.
• [33]Tamai K, Semenov M, Kato Y, Spokony R, Liu C, Katsuyama Y, Hess F, Saint-Jeannet JP, He X: LDL-receptor-related proteins in Wnt signal transduction. Nature 2000, 407:530-535.
• [34]Wehrli M, Dougan ST, Caldwell K, O'Keefe L, Schwartz S, Vaizel-Ohayon D, Schejter E, Tomlinson A, DiNardo S: arrow encodes an LDL-receptor-related protein essential for Wingless signalling. Nature 2000, 407:527-530.
• [35]Hey PJ, Twells RC, Phillips MS, Yusuke N, Brown SD, Kawaguchi Y, Cox R, Guochun X, Dugan V, Hammond H, et al.: Cloning of a novel member of the low-density lipoprotein receptor family. Gene 1998, 216:103-111.
• [36]Twells RC, Mein CA, Payne F, Veijola R, Gilbey M, Bright M, Timms A, Nakagawa Y, Snook H, Nutland S, et al.: Linkage and association mapping of the LRP5 locus on chromosome 11q13 in type 1 diabetes. Hum Genet 2003, 113:99-105.
• [37]Twells RC, Mein CA, Phillips MS, Hess JF, Veijola R, Gilbey M, Bright M, Metzker M, Lie BA, Kingsnorth A, et al.: Haplotype structure, LD blocks, and uneven recombination within the LRP5 gene. Genome Res 2003, 13:845-855.
• [38]Guo YF, Xiong DH, Shen H, Zhao LJ, Xiao P, Guo Y, Wang W, Yang TL, Recker RR, Deng HW: Polymorphisms of the low-density lipoprotein receptor-related protein 5 (LRP5) gene are associated with obesity phenotypes in a large family-based association study. Journal of medical genetics 2006, 43:798-803.
• [39]Fujino T, Asaba H, Kang MJ, Ikeda Y, Sone H, Takada S, Kim DH, Ioka RX, Ono M, Tomoyori H, et al.: Low-density lipoprotein receptor-related protein 5 (LRP5) is essential for normal cholesterol metabolism and glucose-induced insulin secretion. Proc Natl Acad Sci U S A 2003, 100:229-234.
• [40]Kanazawa A, Tsukada S, Sekine A, Tsunoda T, Takahashi A, Kashiwagi A, Tanaka Y, Babazono T, Matsuda M, Kaku K, et al.: Association of the gene encoding wingless-type mammary tumor virus integration-site family member 5B (WNT5B) with type 2 diabetes. Am J Hum Genet 2004, 75:832-843.
• [41]van Tienen FH, Laeremans H, van der Kallen CJ, Smeets HJ: Wnt5b stimulates adipogenesis by activating PPARgamma, and inhibiting the beta-catenin dependent Wnt signaling pathway together with Wnt5a. Biochem Biophys Res Commun 2009, 387:207-211.
• [42]Yang Y, Topol L, Lee H, Wu J: Wnt5a and Wnt5b exhibit distinct activities in coordinating chondrocyte proliferation and differentiation. Development 2003, 130:1003-1015.
• [43]Ross SE, Hemati N, Longo KA, Bennett CN, Lucas PC, Erickson RL, MacDougald OA: Inhibition of adipogenesis by Wnt signaling. Science 2000, 289:950-953.
• [44]Longo KA, Wright WS, Kang S, Gerin I, Chiang SH, Lucas PC, Opp MR, MacDougald OA: Wnt10b inhibits development of white and brown adipose tissues. J Biol Chem 2004, 279:35503-35509.
• [45]Vertino AM, Taylor-Jones JM, Longo KA, Bearden ED, Lane TF, McGehee RE, MacDougald OA, Peterson CA: Wnt10b deficiency promotes coexpression of myogenic and adipogenic programs in myoblasts. Mol Biol Cell 2005, 16:2039-2048.
• [46]Schinner S, Ulgen F, Papewalis C, Schott M, Woelk A, Vidal-Puig A, Scherbaum WA: Regulation of insulin secretion, glucokinase gene transcription and beta cell proliferation by adipocyte-derived Wnt signalling molecules. Diabetologia 2008, 51:147-154.
• [47]Murtaugh LC, Law AC, Dor Y, Melton DA: Beta-catenin is essential for pancreatic acinar but not islet development. Development 2005, 132:4663-4674.
• [48]Papadopoulou S, Edlund H: Attenuated Wnt signaling perturbs pancreatic growth but not pancreatic function. Diabetes 2005, 54:2844-2851.
• [49]Heiser PW, Lau J, Taketo MM, Herrera PL, Hebrok M: Stabilization of beta-catenin impacts pancreas growth. Development 2006, 133:2023-2032.
• [50]Offield MF, Jetton TL, Labosky PA, Ray M, Stein RW, Magnuson MA, Hogan BL, Wright CV: PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development 1996, 122:983-995.
• [51]Rulifson IC, Karnik SK, Heiser PW, ten Berge D, Chen H, Gu X, Taketo MM, Nusse R, Hebrok M, Kim SK: Wnt signaling regulates pancreatic beta cell proliferation. Proc Natl Acad Sci U S A 2007, 104:6247-6252.
• [52]Savic D, Ye H, Aneas I, Park SY, Bell GI, Nobrega MA: Alterations in TCF7L2 expression define its role as a key regulator of glucose metabolism. Genome Res 2011, 21:1417-1425.
• [53]Angus-Hill ML, Elbert KM, Hidalgo J, Capecchi MR: T-cell factor 4 functions as a tumor suppressor whose disruption modulates colon cell proliferation and tumorigenesis. Proc Natl Acad Sci U S A 2011, 108:4914-4919.
• [54]Liu Z, Habener JF: Glucagon-like peptide-1 activation of TCF7L2-dependent Wnt signaling enhances pancreatic beta cell proliferation. J Biol Chem 2008, 283:8723-8735.
• [55]DasGupta R, Fuchs E: Multiple roles for activated LEF/TCF transcription complexes during hair follicle development and differentiation. Development 1999, 126:4557-4568.
• [56]Krutzfeldt J, Stoffel M: Regulation of wingless-type MMTV integration site family (WNT) signalling in pancreatic islets from wild-type and obese mice. Diabetologia 2010, 53:123-127.
• [57]Frayling TM: Genome-wide association studies provide new insights into type 2 diabetes aetiology. Nat Rev Genet 2007, 8:657-662.
• [58]Florez JC: The new type 2 diabetes gene TCF7L2. Curr Opin Clin Nutr Metab Care 2007, 10:391-396.
• [59]Billings LK, Florez JC: The genetics of type 2 diabetes: what have we learned from GWAS? Ann N Y Acad Sci 2010, 1212:59-77.
• [60]Groop L: Open chromatin and diabetes risk. Nat Genet 2010, 42:190-192.
• [61]Duggirala R, Blangero J, Almasy L, Dyer TD, Williams KL, Leach RJ, O'Connell P, Stern MP: Linkage of type 2 diabetes mellitus and of age at onset to a genetic location on chromosome 10q in Mexican Americans. Am J Hum Genet 1999, 64:1127-1140.
• [62]Reynisdottir I, Thorleifsson G, Benediktsson R, Sigurdsson G, Emilsson V, Einarsdottir AS, Hjorleifsdottir EE, Orlygsdottir GT, Bjornsdottir GT, Saemundsdottir J, et al.: Localization of a susceptibility gene for type 2 diabetes to chromosome 5q34–q35.2. Am J Hum Genet 2003, 73:323-335.
• [63]Cauchi S, Meyre D, Choquet H, Dina C, Born C, Marre M, Balkau B, Froguel P: TCF7L2 variation predicts hyperglycemia incidence in a French general population: the data from an epidemiological study on the Insulin Resistance Syndrome (DESIR) study. Diabetes 2006, 55:3189-3192.
• [64]Chang YC, Chang TJ, Jiang YD, Kuo SS, Lee KC, Chiu KC, Chuang LM: Association study of the genetic polymorphisms of the transcription factor 7-like 2 (TCF7L2) gene and type 2 diabetes in the Chinese population. Diabetes 2007, 56:2631-2637.
• [65]Alibegovic AC, Sonne MP, Hojbjerre L, Hansen T, Pedersen O, van Hall G, Holst JJ, Stallknecht B, Dela F, Vaag A: The T-allele of TCF7L2 rs7903146 associates with a reduced compensation of insulin secretion for insulin resistance induced by 9 days of bed rest. Diabetes 2010, 59:836-843.
• [66]Cornelis MC, Qi L, Kraft P, Hu FB: TCF7L2, dietary carbohydrate, and risk of type 2 diabetes in US women. Am J Clin Nutr 2009, 89:1256-1262.
• [67]da Silva Xavier G, Loder MK, McDonald A, Tarasov AI, Carzaniga R, Kronenberger K, Barg S, Rutter GA: TCF7L2 regulates late events in insulin secretion from pancreatic islet beta-cells. Diabetes 2009, 58:894-905.
• [68]Dabelea D, Dolan LM, D'Agostino R, Hernandez AM, McAteer JB, Hamman RF, Mayer-Davis EJ, Marcovina S, Lawrence JM, Pihoker C, Florez JC: Association testing of TCF7L2 polymorphisms with type 2 diabetes in multi-ethnic youth. Diabetologia 2011, 54:535-539.
• [69]Duan QL, Dube MP, Frasure-Smith N, Barhdadi A, Lesperance F, Theroux P, St-Onge J, Rouleau GA, McCaffery JM: Additive effects of obesity and TCF7L2 variants on risk for type 2 diabetes among cardiac patients. Diabetes Care 2007, 30:1621-1623.
• [70]Florez JC: Newly identified loci highlight beta cell dysfunction as a key cause of type 2 diabetes: where are the insulin resistance genes? Diabetologia 2008, 51:1100-1110.
• [71]Florez JC, Jablonski KA, Bayley N, Pollin TI, de Bakker PI, Shuldiner AR, Knowler WC, Nathan DM, Altshuler D: TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program. N Engl J Med 2006, 355:241-250.
• [72]Gjesing AP, Kjems LL, Vestmar MA, Grarup N, Linneberg A, Deacon CF, Holst JJ, Pedersen O, Hansen T: Carriers of the TCF7L2 rs7903146 TT genotype have elevated levels of plasma glucose, serum proinsulin and plasma gastric inhibitory polypeptide (GIP) during a meal test. Diabetologia 2011, 54:103-110.
• [73]Gloyn AL, Braun M, Rorsman P: Type 2 diabetes susceptibility gene TCF7L2 and its role in beta-cell function. Diabetes 2009, 58:800-802.
• [74]Gonzalez-Sanchez JL, Martinez-Larrad MT, Zabena C, Perez-Barba M, Serrano-Rios M: Association of variants of the TCF7L2 gene with increases in the risk of type 2 diabetes and the proinsulin:insulin ratio in the Spanish population. Diabetologia 2008, 51:1993-1997.
• [75]Ng MC, Park KS, Oh B, Tam CH, Cho YM, Shin HD, Lam VK, Ma RC, So WY, Cho YS, et al.: Implication of genetic variants near TCF7L2, SLC30A8, HHEX, CDKAL1, CDKN2A/B, IGF2BP2, and FTO in type 2 diabetes and obesity in 6,719 Asians. Diabetes 2008, 57:2226-2233.
• [76]Pilgaard K, Jensen CB, Schou JH, Lyssenko V, Wegner L, Brons C, Vilsboll T, Hansen T, Madsbad S, Holst JJ, et al.: The T allele of rs7903146 TCF7L2 is associated with impaired insulinotropic action of incretin hormones, reduced 24 h profiles of plasma insulin and glucagon, and increased hepatic glucose production in young healthy men. Diabetologia 2009, 52:1298-1307.
• [77]Vacik T, Stubbs JL, Lemke G: A novel mechanism for the transcriptional regulation of Wnt signaling in development. Genes Dev 2011, 25:1783-1795.
• [78]Le Bacquer O, Shu L, Marchand M, Neve B, Paroni F, Kerr Conte J, Pattou F, Froguel P, Maedler K: TCF7L2 splice variants have distinct effects on beta-cell turnover and function. Hum Mol Genet 2011, 20:1906-1915.
• [79]Prokunina-Olsson L, Welch C, Hansson O, Adhikari N, Scott LJ, Usher N, Tong M, Sprau A, Swift A, Bonnycastle LL, et al.: Tissue-specific alternative splicing of TCF7L2. Hum Mol Genet 2009, 18:3795-3804.
• [80]Ni Z, Anini Y, Fang X, Mills G, Brubaker PL, Jin T: Transcriptional activation of the proglucagon gene by lithium and beta-catenin in intestinal endocrine L cells. J Biol Chem 2003, 278:1380-1387.
• [81]Yi F, Sun J, Lim GE, Fantus IG, Brubaker PL, Jin T: Cross talk between the insulin and Wnt signaling pathways: evidence from intestinal endocrine L cells. Endocrinology 2008, 149:2341-2351.
• [82]Cho YM, Kieffer TJ: K-cells and glucose-dependent insulinotropic polypeptide in health and disease. Vitam Horm 2010, 84:111-150.
• [83]Garcia-Martinez JM, Chocarro-Calvo A, Moya CM, Garcia-Jimenez C: WNT/beta-catenin increases the production of incretins by entero-endocrine cells. Diabetologia 2009, 52:1913-1924.
• [84]Gustafson B, Smith U: WNT signalling is both an inducer and effector of glucagon-like peptide-1. Diabetologia 2008, 51:1768-1770.
• [85]Garcia-Jimenez C: Wnt and incretin connections. Vitam Horm 2010, 84:355-387.
• [86]Gebhardt R, Hovhannisyan A: Organ patterning in the adult stage: the role of Wnt/beta-catenin signaling in liver zonation and beyond. Dev Dyn 2010, 239:45-55.
• [87]Liu H, Fergusson MM, Wu JJ, Rovira II, Liu J, Gavrilova O, Lu T, Bao J, Han D, Sack MN, Finkel T: Wnt signaling regulates hepatic metabolism. Sci Signal 2011, 4:ra6.
• [88]Norton L, Fourcaudot M, Abdul-Ghani MA, Winnier D, Mehta FF, Jenkinson CP, Defronzo RA: Chromatin occupancy of transcription factor 7-like 2 (TCF7L2) and its role in hepatic glucose metabolism. Diabetologia 2011.
• [89]Ahlzen M, Johansson LE, Cervin C, Tornqvist H, Groop L, Ridderstrale M: Expression of the transcription factor 7-like 2 gene (TCF7L2) in human adipocytes is down regulated by insulin. Biochem Biophys Res Commun 2008, 370:49-52.
• [90]Brinkmeier ML, Potok MA, Davis SW, Camper SA: TCF4 deficiency expands ventral diencephalon signaling and increases induction of pituitary progenitors. Dev Biol 2007, 311:396-407.
• [91]Baggio LL, Drucker DJ: Biology of incretins: GLP-1 and GIP. Gastroenterology 2007, 132:2131-2157.
• [92]Turton MD, O'Shea D, Gunn I, Beak SA, Edwards CM, Meeran K, Choi SJ, Taylor GM, Heath MM, Lambert PD, et al.: A role for glucagon-like peptide-1 in the central regulation of feeding. Nature 1996, 379:69-72.
• [93]Greer EL, Brunet A: FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene 2005, 24:7410-7425.
• [94]Accili D, Arden KC: FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. Cell 2004, 117:421-426.
• [95]Essers MA, de Vries-Smits LM, Barker N, Polderman PE, Burgering BM, Korswagen HC: Functional interaction between beta-catenin and FOXO in oxidative stress signaling. Science 2005, 308:1181-1184.
• [96]Basu S, Michaelsson K, Olofsson H, Johansson S, Melhus H: Association between oxidative stress and bone mineral density. Biochem Biophys Res Commun 2001, 288:275-279.
• [97]Almeida M, Han L, Ambrogini E, Weinstein RS, Manolagas SC: Glucocorticoids and tumor necrosis factor alpha increase oxidative stress and suppress Wnt protein signaling in osteoblasts. J Biol Chem 2011, 286:44326-44335.
• [98]Almeida M, Ambrogini E, Han L, Manolagas SC, Jilka RL: Increased lipid oxidation causes oxidative stress, increased peroxisome proliferator-activated receptor-gamma expression, and diminished pro-osteogenic Wnt signaling in the skeleton. J Biol Chem 2009, 284:27438-27448.
• [99]Almeida M: Unraveling the role of FoxOs in bone–insights from mouse models. Bone 2011, 49:319-327.
• [100]Malbon CC: Beta-catenin, cancer, and G proteins: not just for frizzleds anymore. Sci STKE 2005, 2005:pe35.