Retinoic Acid-Related Orphan Receptor γ (RORγ): A Novel Participant in the Diurnal Regulation of Hepatic Gluconeogenesis and Insulin Sensitivity

English version České info

The circadian clock plays a critical role in the regulation of many physiological processes, including metabolism and energy homeostasis. The retinoic acid-related orphan receptor γ (RORγ) functions as a ligand-dependent transcription factor that regulates transcription by binding as a monomer to ROR-responsive elements. In liver, RORγ exhibits a robust circadian pattern of expression that is under direct control of the hepatic circadian clock. However, the connection between the circadian regulation of RORγ and its control of downstream metabolic processes is not well understood. In this study, by using ubiquitous and liver-specific RORγ-deficient mice as models, we demonstrate that hepatic RORγ modulates daily insulin sensitivity and glucose tolerance by regulating hepatic gluconeogenesis. Genome-wide cistromic profiling, gene expression, and promoter analysis revealed that RORγ is targeting and regulating a number of novel metabolic genes critical in the control of glycolysis and gluconeogenesis pathways. We provide evidence for a model in which RORγ regulates the circadian expression of glucose metabolic genes in the liver downstream of the hepatic circadian clock, thereby enhancing gluconeogenesis and decreasing insulin sensitivity and glucose tolerance. This study suggests that attenuating RORγ activity by antagonists might be beneficial for the management of glucose metabolic diseases including type 2 diabetes.

Vyšlo v časopise: Retinoic Acid-Related Orphan Receptor γ (RORγ): A Novel Participant in the Diurnal Regulation of Hepatic Gluconeogenesis and Insulin Sensitivity. PLoS Genet 10(5): e32767. doi:10.1371/journal.pgen.1004331
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004331

Souhrn

Zdroje

1. JettenAM (2009) Retinoid-related orphan receptors (RORs): critical roles in development, immunity, circadian rhythm, and cellular metabolism. Nucl Recept Signal 7: e003.

2. FitzsimmonsRL, LauP, MuscatGE (2012) Retinoid-related orphan receptor alpha and the regulation of lipid homeostasis. J Steroid Biochem Mol Biol 130 : 159–168.

3. YangXO, PappuBP, NurievaR, AkimzhanovA, KangHS, et al. (2008) T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity 28 : 29–39.

4. HuhJR, LeungMW, HuangP, RyanDA, KroutMR, et al. (2011) Digoxin and its derivatives suppress TH17 cell differentiation by antagonizing RORgammat activity. Nature 472 : 486–490.

5. EberlG, LittmanDR (2003) The role of the nuclear hormone receptor RORgammat in the development of lymph nodes and Peyer's patches. Immunol Rev 195 : 81–90.

6. SoltLA, KojetinDJ, BurrisTP (2011) The REV-ERBs and RORs: molecular links between circadian rhythms and lipid homeostasis. Future Med Chem 3 : 623–638.

7. AkashiM, TakumiT (2005) The orphan nuclear receptor RORalpha regulates circadian transcription of the mammalian core-clock Bmal1. Nat Struct Mol Biol 12 : 441–448.

8. TakedaY, KangHS, AngersM, JettenAM (2011) Retinoic acid-related orphan receptor gamma directly regulates neuronal PAS domain protein 2 transcription in vivo. Nucleic Acids Res 39 : 4769–4782.

9. MongrainV, RuanX, DardenteH, FortierEE, CermakianN (2008) Clock-dependent and independent transcriptional control of the two isoforms from the mouse Rorgamma gene. Genes Cells 13 : 1197–1210.

10. TakedaY, JothiR, BiraultV, JettenAM (2012) RORgamma directly regulates the circadian expression of clock genes and downstream targets in vivo. Nucleic Acids Res 40 : 8519–8535.

11. UedaHR, HayashiS, ChenW, SanoM, MachidaM, et al. (2005) System-level identification of transcriptional circuits underlying mammalian circadian clocks. Nat Genet 37 : 187–192.

12. LiuAC, TranHG, ZhangEE, PriestAA, WelshDK, et al. (2008) Redundant function of REV-ERBalpha and beta and non-essential role for Bmal1 cycling in transcriptional regulation of intracellular circadian rhythms. PLoS Genet 4: e1000023.

13. DuezH, StaelsB (2010) Nuclear receptors linking circadian rhythms and cardiometabolic control. Arterioscler Thromb Vasc Biol 30 : 1529–1534.

14. ChoH, ZhaoX, HatoriM, YuRT, BarishGD, et al. (2012) Regulation of circadian behaviour and metabolism by REV-ERB-alpha and REV-ERB-beta. Nature 485 : 123–127.

15. ReyG, CesbronF, RougemontJ, ReinkeH, BrunnerM, et al. (2011) Genome-wide and phase-specific DNA-binding rhythms of BMAL1 control circadian output functions in mouse liver. PLoS Biol 9: e1000595.

16. BassJ, TakahashiJS (2010) Circadian integration of metabolism and energetics. Science 330 : 1349–1354.

17. Eckel-MahanK, Sassone-CorsiP (2013) Metabolism and the circadian clock converge. Physiol Rev 93 : 107–135.

18. AsherG, SchiblerU (2011) Crosstalk between components of circadian and metabolic cycles in mammals. Cell Metab 13 : 125–137.

19. RippergerJA, AlbrechtU (2012) REV-ERB-erating nuclear receptor functions in circadian metabolism and physiology. Cell Res 22 : 1319–1321.

20. MeissburgerB, UkropecJ, RoederE, BeatonN, GeigerM, et al. (2011) Adipogenesis and insulin sensitivity in obesity are regulated by retinoid-related orphan receptor gamma. EMBO Mol Med 3 : 637–651.

21. TinahonesFJ, Moreno-SantosI, VendrellJ, ChaconMR, Garrido-SanchezL, et al. (2012) The retinoic acid receptor-related orphan nuclear receptor gamma1 (RORgamma1): a novel player determinant of insulin sensitivity in morbid obesity. Obesity 20 : 488–497.

22. JettenAM, KangHS, TakedaY (2013) Retinoic acid-related orphan receptors alpha and gamma: key regulators of lipid/glucose metabolism, inflammation, and insulin sensitivity. Front Endocrinol 4 : 1.

23. RudicRD, McNamaraP, CurtisAM, BostonRC, PandaS, et al. (2004) BMAL1 and CLOCK, two essential components of the circadian clock, are involved in glucose homeostasis. PLoS Biol 2: e377.

24. ShiSQ, AnsariTS, McGuinnessOP, WassermanDH, JohnsonCH (2013) Circadian Disruption Leads to Insulin Resistance and Obesity. Curr Biol 23 : 372–381.

25. ClarkPW, JenkinsAB, KraegenEW (1990) Pentobarbital reduces basal liver glucose output and its insulin suppression in rats. Am J Physiol 258: E701–707.

26. BassJ (2012) Circadian topology of metabolism. Nature 491 : 348–356.

27. BurgessSC, JeffreyFM, StoreyC, MildeA, HauslerN, et al. (2005) Effect of murine strain on metabolic pathways of glucose production after brief or prolonged fasting. Am J Physiol Endocrinol Metab 289: E53–61.

28. BuggeA, FengD, EverettLJ, BriggsER, MullicanSE, et al. (2012) Rev-erbalpha and Rev-erbbeta coordinately protect the circadian clock and normal metabolic function. Genes Dev 26 : 657–667.

29. KangHS, AngersM, BeakJY, WuX, GimbleJM, et al. (2007) Gene expression profiling reveals a regulatory role for ROR alpha and ROR gamma in phase I and phase II metabolism. Physiol Genomics 31 : 281–294.

30. LiuS, HatanoB, ZhaoM, YenCC, KangK, et al. (2011) Role of peroxisome proliferator-activated receptor {delta}/{beta} in hepatic metabolic regulation. J Biol Chem 286 : 1237–1247.

31. ChopraAR, LouetJF, SahaP, AnJ, DemayoF, et al. (2008) Absence of the SRC-2 coactivator results in a glycogenopathy resembling Von Gierke's disease. Science 322 : 1395–1399.

32. ImSS, KimMY, KwonSK, KimTH, BaeJS, et al. (2011) Peroxisome proliferator-activated receptor {alpha} is responsible for the up-regulation of hepatic glucose-6-phosphatase gene expression in fasting and db/db Mice. J Biol Chem 286 : 1157–1164.

33. YangX, DownesM, YuRT, BookoutAL, HeW, et al. (2006) Nuclear receptor expression links the circadian clock to metabolism. Cell 126 : 801–810.

34. GiguereV, TiniM, FlockG, OngE, EvansRM, et al. (1994) Isoform-specific amino-terminal domains dictate DNA-binding properties of ROR alpha, a novel family of orphan hormone nuclear receptors. Genes Dev 8 : 538–553.

35. MedvedevA, YanZH, HiroseT, GiguereV, JettenAM (1996) Cloning of a cDNA encoding the murine orphan receptor RZR/ROR gamma and characterization of its response element. Gene 181 : 199–206.

36. KurebayashiS, UedaE, SakaueM, PatelDD, MedvedevA, et al. (2000) Retinoid-related orphan receptor gamma (RORgamma) is essential for lymphoid organogenesis and controls apoptosis during thymopoiesis. Proc Natl Acad Sci USA 97 : 10132–10137.

37. NarlikarL, JothiR (2012) ChIP-Seq data analysis: identification of protein-DNA binding sites with SISSRs peak-finder. Meth Mol Biol 802 : 305–322.

38. JothiR, CuddapahS, BarskiA, CuiK, ZhaoK (2008) Genome-wide identification of in vivo protein-DNA binding sites from ChIP-Seq data. Nucleic Acids Res 36 : 5221–5231.