TCF7L2 Modulates Glucose Homeostasis by Regulating CREB- and FoxO1-Dependent Transcriptional Pathway in the Liver


Peripheral insulin resistance contributes to the development of type 2 diabetes. TCF7L2 has been tightly associated with this disease, although the exact mechanism was largely elusive. Here we propose a novel role of TCF7L2 in hepatic glucose metabolism in mammals. Expression of medium and short isoforms of TCF7L2 was greatly diminished in livers of diet-induced and genetic mouse models of insulin resistance, prompting us to delineate the functional role of these isoforms in hepatic glucose metabolism. Knockdown of hepatic TCF7L2 promoted increased blood glucose levels and glucose intolerance with increased gluconeogenic gene expression in wild-type mice, in accordance with the PCR array data showing that only the gluconeogenic pathway is specifically up-regulated upon depletion of hepatic TCF7L2. Conversely, overexpression of a nuclear isoform of TCF7L2 in high-fat diet-fed mice ameliorated hyperglycemia with improved glucose tolerance, suggesting a role of this factor in hepatic glucose metabolism. Indeed, we observed a binding of TCF7L2 to promoters of gluconeogenic genes; and expression of TCF7L2 inhibited adjacent promoter occupancies of CREB, CRTC2, and FoxO1, critical transcriptional modules in hepatic gluconeogenesis, to disrupt target gene transcription. Finally, haploinsufficiency of TCF7L2 in mice displayed higher glucose levels and impaired glucose tolerance, which were rescued by hepatic expression of a nuclear isoform of TCF7L2 at the physiological level. Collectively, these data suggest a crucial role of TCF7L2 in hepatic glucose metabolism; reduced hepatic expression of nuclear isoforms of this factor might be a critical instigator of hyperglycemia in type 2 diabetes.


Vyšlo v časopise: TCF7L2 Modulates Glucose Homeostasis by Regulating CREB- and FoxO1-Dependent Transcriptional Pathway in the Liver. PLoS Genet 8(9): e32767. doi:10.1371/journal.pgen.1002986
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.pgen.1002986

Souhrn

Peripheral insulin resistance contributes to the development of type 2 diabetes. TCF7L2 has been tightly associated with this disease, although the exact mechanism was largely elusive. Here we propose a novel role of TCF7L2 in hepatic glucose metabolism in mammals. Expression of medium and short isoforms of TCF7L2 was greatly diminished in livers of diet-induced and genetic mouse models of insulin resistance, prompting us to delineate the functional role of these isoforms in hepatic glucose metabolism. Knockdown of hepatic TCF7L2 promoted increased blood glucose levels and glucose intolerance with increased gluconeogenic gene expression in wild-type mice, in accordance with the PCR array data showing that only the gluconeogenic pathway is specifically up-regulated upon depletion of hepatic TCF7L2. Conversely, overexpression of a nuclear isoform of TCF7L2 in high-fat diet-fed mice ameliorated hyperglycemia with improved glucose tolerance, suggesting a role of this factor in hepatic glucose metabolism. Indeed, we observed a binding of TCF7L2 to promoters of gluconeogenic genes; and expression of TCF7L2 inhibited adjacent promoter occupancies of CREB, CRTC2, and FoxO1, critical transcriptional modules in hepatic gluconeogenesis, to disrupt target gene transcription. Finally, haploinsufficiency of TCF7L2 in mice displayed higher glucose levels and impaired glucose tolerance, which were rescued by hepatic expression of a nuclear isoform of TCF7L2 at the physiological level. Collectively, these data suggest a crucial role of TCF7L2 in hepatic glucose metabolism; reduced hepatic expression of nuclear isoforms of this factor might be a critical instigator of hyperglycemia in type 2 diabetes.


Zdroje

1. ChoH, MuJ, KimJK, ThorvaldsenJL, ChuQ, et al. (2001) Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science 292: 1728–1731.

2. TaniguchiCM, KondoT, SajanM, LuoJ, BronsonR, et al. (2006) Divergent regulation of hepatic glucose and lipid metabolism by phosphoinositide 3-kinase via Akt and PKClambda/zeta. Cell Metab 3: 343–353.

3. WanM, LeavensKF, SalehD, EastonRM, GuertinDA, et al. (2011) Postprandial hepatic lipid metabolism requires signaling through Akt2 independent of the transcription factors FoxA2, FoxO1, and SREBP1c. Cell Metab 14: 516–527.

4. SaltielAR, KahnCR (2001) Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414: 799–806.

5. AriasJ, AlbertsAS, BrindleP, ClaretFX, SmealT, et al. (1994) Activation of cAMP and mitogen responsive genes relies on a common nuclear factor. Nature 370: 226–229.

6. ChriviaJC, KwokRP, LambN, HagiwaraM, MontminyMR, et al. (1993) Phosphorylated CREB binds specifically to the nuclear protein CBP. Nature 365: 855–859.

7. KwokRP, LundbladJR, ChriviaJC, RichardsJP, BachingerHP, et al. (1994) Nuclear protein CBP is a coactivator for the transcription factor CREB. Nature 370: 223–226.

8. HerzigS, LongF, JhalaUS, HedrickS, QuinnR, et al. (2001) CREB regulates hepatic gluconeogenesis through the coactivator PGC-1. Nature 413: 179–183.

9. QuinnPG, GrannerDK (1990) Cyclic AMP-dependent protein kinase regulates transcription of the phosphoenolpyruvate carboxykinase gene but not binding of nuclear factors to the cyclic AMP regulatory element. Mol Cell Biol 10: 3357–3364.

10. ShortJM, Wynshaw-BorisA, ShortHP, HansonRW (1986) Characterization of the phosphoenolpyruvate carboxykinase (GTP) promoter-regulatory region. II. Identification of cAMP and glucocorticoid regulatory domains. J Biol Chem 261: 9721–9726.

11. DentinR, LiuY, KooSH, HedrickS, VargasT, et al. (2007) Insulin modulates gluconeogenesis by inhibition of the coactivator TORC2. Nature 449: 366–369.

12. KooSH, FlechnerL, QiL, ZhangX, ScreatonRA, et al. (2005) The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature 437: 1109–1111.

13. HeL, SabetA, DjedjosS, MillerR, SunX, et al. (2009) Metformin and insulin suppress hepatic gluconeogenesis through phosphorylation of CREB binding protein. Cell 137: 635–646.

14. RavnskjaerK, KesterH, LiuY, ZhangX, LeeD, et al. (2007) Cooperative interactions between CBP and TORC2 confer selectivity to CREB target gene expression. EMBO J 26: 2880–2889.

15. ShawRJ, LamiaKA, VasquezD, KooSH, BardeesyN, et al. (2005) The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310: 1642–1646.

16. MihaylovaMM, VasquezDS, RavnskjaerK, DenechaudPD, YuRT, et al. (2011) Class IIa histone deacetylases are hormone-activated regulators of FOXO and mammalian glucose homeostasis. Cell 145: 607–621.

17. YoonJC, PuigserverP, ChenG, DonovanJ, WuZ, et al. (2001) Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 413: 131–138.

18. PuigserverP, RheeJ, DonovanJ, WalkeyCJ, YoonJC, et al. (2003) Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction. Nature 423: 550–555.

19. LuM, WanM, LeavensKF, ChuQ, MonksBR, et al. (2012) Insulin regulates liver metabolism in vivo in the absence of hepatic Akt and Foxo1. Nat Med 18: 388–395.

20. Le LayJ, TutejaG, WhiteP, DhirR, AhimaR, et al. (2009) CRTC2 (TORC2) contributes to the transcriptional response to fasting in the liver but is not required for the maintenance of glucose homeostasis. Cell Metab 10: 55–62.

21. WangY, InoueH, RavnskjaerK, VisteK, MillerN, et al. (2010) Targeted disruption of the CREB coactivator Crtc2 increases insulin sensitivity. Proc Natl Acad Sci U S A 107: 3087–3092.

22. RubinfeldB, RobbinsP, El-GamilM, AlbertI, PorfiriE, et al. (1997) Stabilization of beta-catenin by genetic defects in melanoma cell lines. Science 275: 1790–1792.

23. BehrensJ, von KriesJP, KuhlM, BruhnL, WedlichD, et al. (1996) Functional interaction of beta-catenin with the transcription factor LEF-1. Nature 382: 638–642.

24. MolenaarM, van de WeteringM, OosterwegelM, Peterson-MaduroJ, GodsaveS, et al. (1996) XTcf-3 transcription factor mediates beta-catenin-induced axis formation in Xenopus embryos. Cell 86: 391–399.

25. HuberO, KornR, McLaughlinJ, OhsugiM, HerrmannBG, et al. (1996) Nuclear localization of beta-catenin by interaction with transcription factor LEF-1. Mech Dev 59: 3–10.

26. ReyaT, CleversH (2005) Wnt signalling in stem cells and cancer. Nature 434: 843–850.

27. CleversH (2006) Wnt/beta-catenin signaling in development and disease. Cell 127: 469–480.

28. ChandakGR, JanipalliCS, BhaskarS, KulkarniSR, MohankrishnaP, et al. (2007) Common variants in the TCF7L2 gene are strongly associated with type 2 diabetes mellitus in the Indian population. Diabetologia 50: 63–67.

29. GrantSF, ThorleifssonG, ReynisdottirI, BenediktssonR, ManolescuA, et al. (2006) Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet 38: 320–323.

30. HayashiT, IwamotoY, KakuK, HiroseH, MaedaS (2007) Replication study for the association of TCF7L2 with susceptibility to type 2 diabetes in a Japanese population. Diabetologia 50: 980–984.

31. HorikoshiM, HaraK, ItoC, NagaiR, FroguelP, et al. (2007) A genetic variation of the transcription factor 7-like 2 gene is associated with risk of type 2 diabetes in the Japanese population. Diabetologia 50: 747–751.

32. LehmanDM, HuntKJ, LeachRJ, HamlingtonJ, AryaR, et al. (2007) Haplotypes of transcription factor 7-like 2 (TCF7L2) gene and its upstream region are associated with type 2 diabetes and age of onset in Mexican Americans. Diabetes 56: 389–393.

33. ZegginiE, McCarthyMI (2007) TCF7L2: the biggest story in diabetes genetics since HLA? Diabetologia 50: 1–4.

34. HelgasonA, PalssonS, ThorleifssonG, GrantSF, EmilssonV, et al. (2007) Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution. Nat Genet 39: 218–225.

35. ChoYM, KimTH, LimS, ChoiSH, ShinHD, et al. (2009) Type 2 diabetes-associated genetic variants discovered in the recent genome-wide association studies are related to gestational diabetes mellitus in the Korean population. Diabetologia 52: 253–261.

36. ShuL, SauterNS, SchulthessFT, MatveyenkoAV, OberholzerJ, et al. (2008) Transcription factor 7-like 2 regulates beta-cell survival and function in human pancreatic islets. Diabetes 57: 645–653.

37. YiF, BrubakerPL, JinT (2005) TCF-4 mediates cell type-specific regulation of proglucagon gene expression by beta-catenin and glycogen synthase kinase-3beta. J Biol Chem 280: 1457–1464.

38. CauchiS, ChoquetH, Gutierrez-AguilarR, CapelF, GrauK, et al. (2008) Effects of TCF7L2 polymorphisms on obesity in European populations. Obesity (Silver Spring) 16: 476–482.

39. CauchiS, MeyreD, ChoquetH, DinaC, BornC, et al. (2006) TCF7L2 variation predicts hyperglycemia incidence in a French general population: the data from an epidemiological study on the Insulin Resistance Syndrome (DESIR) study. Diabetes 55: 3189–3192.

40. CauchiS, MeyreD, DinaC, ChoquetH, SamsonC, et al. (2006) Transcription factor TCF7L2 genetic study in the French population: expression in human beta-cells and adipose tissue and strong association with type 2 diabetes. Diabetes 55: 2903–2908.

41. FlorezJC, JablonskiKA, BayleyN, PollinTI, de BakkerPI, et al. (2006) TCF7L2 polymorphisms and progression to diabetes in the Diabetes Prevention Program. N Engl J Med 355: 241–250.

42. ElbeinSC, ChuWS, DasSK, Yao-BorengasserA, HasstedtSJ, et al. (2007) Transcription factor 7-like 2 polymorphisms and type 2 diabetes, glucose homeostasis traits and gene expression in US participants of European and African descent. Diabetologia 50: 1621–1630.

43. OsmarkP, HanssonO, JonssonA, RonnT, GroopL, et al. (2009) Unique splicing pattern of the TCF7L2 gene in human pancreatic islets. Diabetologia 52: 850–854.

44. Prokunina-OlssonL, WelchC, HanssonO, AdhikariN, ScottLJ, et al. (2009) Tissue-specific alternative splicing of TCF7L2. Hum Mol Genet 18: 3795–3804.

45. LyssenkoV, LupiR, MarchettiP, Del GuerraS, Orho-MelanderM, et al. (2007) Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes. J Clin Invest 117: 2155–2163.

46. Prokunina-OlssonL, KaplanLM, SchadtEE, CollinsFS (2009) Alternative splicing of TCF7L2 gene in omental and subcutaneous adipose tissue and risk of type 2 diabetes. PLoS ONE 4: e7231 doi:10.1371/journal.pone.0007231.

47. WeiseA, BruserK, ElfertS, WallmenB, WittelY, et al. (2010) Alternative splicing of Tcf7l2 transcripts generates protein variants with differential promoter-binding and transcriptional activation properties at Wnt/beta-catenin targets. Nucleic Acids Res 38: 1964–1981.

48. SavicD, YeH, AneasI, ParkSY, BellGI, et al. (2011) Alterations in TCF7L2 expression define its role as a key regulator of glucose metabolism. Genome Res 21: 1417–1425.

49. NortonL, FourcaudotM, Abdul-GhaniMA, WinnierD, MehtaFF, et al. (2011) Chromatin occupancy of transcription factor 7-like 2 (TCF7L2) and its role in hepatic glucose metabolism. Diabetologia 54: 3132–3142.

50. BurgessSC, HeT, YanZ, LindnerJ, SherryAD, et al. (2007) Cytosolic phosphoenolpyruvate carboxykinase does not solely control the rate of hepatic gluconeogenesis in the intact mouse liver. Cell Metab 5: 313–320.

51. SchmollD, WasnerC, HindsCJ, AllanBB, WaltherR, et al. (1999) Identification of a cAMP response element within the glucose- 6-phosphatase hydrolytic subunit gene promoter which is involved in the transcriptional regulation by cAMP and glucocorticoids in H4IIE hepatoma cells. Biochem J 338(Pt 2):457–463.

52. HeTC, ZhouS, da CostaLT, YuJ, KinzlerKW, et al. (1998) A simplified system for generating recombinant adenoviruses. Proc Natl Acad Sci U S A 95: 2509–2514.

53. KooSH, SatohH, HerzigS, LeeCH, HedrickS, et al. (2004) PGC-1 promotes insulin resistance in liver through PPAR-alpha-dependent induction of TRB-3. Nat Med 10: 530–534.

54. FolchJ, LeesM, Sloane StanleyGH (1957) A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem 226: 497–509.

55. ChoiCS, SavageDB, Abu-ElheigaL, LiuZX, KimS, et al. (2007) Continuous fat oxidation in acetyl-CoA carboxylase 2 knockout mice increases total energy expenditure, reduces fat mass, and improves insulin sensitivity. Proc Natl Acad Sci U S A 104: 16480–16485.

56. RyuD, OhKJ, JoHY, HedrickS, KimYN, et al. (2009) TORC2 regulates hepatic insulin signaling via a mammalian phosphatidic acid phosphatase, LIPIN1. Cell Metab 9: 240–251.

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2012 Číslo 9
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Eozinofilní granulomatóza s polyangiitidou
nový kurz

Betablokátory a Ca antagonisté z jiného úhlu
Autori: prof. MUDr. Michal Vrablík, Ph.D., MUDr. Petr Janský

Autori: doc. MUDr. Petr Čáp, Ph.D.

Farmakoterapie akutní a chronické bolesti

Získaná hemofilie - Povědomí o nemoci a její diagnostika

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Nemáte účet?  Registrujte sa

Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa