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- W3199720741 abstract "Testicular Receptor 4 (TR4, NR2C2), an orphanmember of the nuclear receptor superfamily, is known to be involvedin postnatal growth, neural development, spermatogenesis, and manysignal pathways. However, the physiological roles of TR4 inglucose, lipid metabolism, and insulin sensitivity remain unclear.Our studies revealed novel roles of TR4 in glucose and lipidmetabolism. Hepatic gluconeogenesis is robustly activated inresponse to fasting, in which phosphoenolpyruvate carboxykinase(PEPCK) is the important gene regulating the de novo glucoseproduction process. We found hypoglycemia in mice lacking TR4(TR4-/-) with reduced PEPCK gene expression during fasting.Overexpression of TR4 induced PEPCK gene transcription and led toincreased hepatic glucose production. Furthermore, mechanisticdissection suggested TR4 binds to the PEPCK gene promoter andinduces its expression via a transcriptional regulation. Inresponse to fasting, the hepatic expression of TR4 and theassociation of TR4 with PEPCK promoter were induced by the cAMP/PKAaxis and C/EBPs leading to increased PEPCK expression and elevatedgluconeogenesis. In addition to the up-regulated TR4 expression, weinvestigated other mechanisms regulating TR4 biological activity.Here we showed that, in the absence of specific ligand(s), theactivity of TR4 could be modulated by metformin via AMP-activatedprotein kinase (AMPK)-mediated phosphorylation. This demonstratedthat TR4 is a downstream target of metformin/AMPK signaling pathwayand raised the possibility that small molecule(s) can modulate TR4activity through AMPK. Stearoyl-CoA desaturase 1 (SCD1) is acritical regulator in the biosynthesis of monounsaturated fattyacid. Previous studies suggest that both SREBP-1c-dependent and-independent regulation could control SCD1 gene expression.However, the mechanisms of SREBP-1c-independent regulation on SCD1remain unclear. We demonstrated that SCD1 was induced by TR4 in aSREBP-1c-independent manner. Deficiency of SCD1 in TR4-/- miceresulted in less fat mass and increased insulin sensitivity withaltered β-oxidation and lipogenesis. Knockdown of TR4 via RNAi inwild-type mouse primary hepatocytes resulted in reduction of SCD1.Together, our results showed that modulation of TR4 via geneticknockout, RNAi knockdown, or phosphonyl inactivation, all affectSCD1 transcription, demonstrating a novel SREBP-1c-independentpathway to modulate SCD1 gene expression." @default.
- W3199720741 created "2021-09-27" @default.
- W3199720741 creator A5060718942 @default.
- W3199720741 date "2009-01-01" @default.
- W3199720741 modified "2023-09-27" @default.
- W3199720741 title "Analysis of TR4 orphan nuclear receptor knockout mouse:roles of TR4 in glucose and lipid metabolism" @default.
- W3199720741 hasPublicationYear "2009" @default.
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