title: CRTC2 Is a Coactivator of GR and Couples GR and CREB in the Regulation of Hepatic Gluconeogenesis.
abstract: Glucocorticoid hormones play essential roles in the regulation of gluconeogenesis in the liver, an adaptive response that is required for the maintenance of circulating glucose levels during fasting. Glucocorticoids do this by cooperating with glucagon, which is secreted from pancreatic islets to activate the cAMP-signaling pathway in hepatocytes. The cAMP-response element-binding protein (CREB)-regulated transcription coactivator 2 (CRTC2) is a coactivator known to be specific to CREB and plays a central role in the glucagon-mediated activation of gluconeogenesis in the early phase of fasting. We show here that CRTC2 also functions as a coactivator for the glucocorticoid receptor (GR). CRTC2 strongly enhances GR-induced transcriptional activity of glucocorticoid-responsive genes. CRTC2 physically interacts with the ligand-binding domain of the GR through a region spanning amino acids 561-693. Further, CRTC2 is required for the glucocorticoid-associated cooperative mRNA expression of the glucose-6-phosphatase, a rate-limiting enzyme for hepatic gluconeogenesis, by facilitating the attraction of GR and itself to its promoter region already occupied by CREB. CRTC2 is required for the maintenance of blood glucose levels during fasting in mice by enhancing the GR transcriptional activity on both the G6p and phosphoenolpyruvate carboxykinase (Pepck) genes. Finally, CRTC2 modulates the transcriptional activity of the progesterone receptor, indicating that it may influence the transcriptional activity of other steroid/nuclear receptors. Taken together, these results reveal that CRTC2 plays an essential role in the regulation of hepatic gluconeogenesis through coordinated regulation of the glucocorticoid/GR- and glucagon/CREB-signaling pathways on the key genes G6P and PEPCK.
authors.affiliation: Program in Reproductive and Adult Endocrinology (M.J.H., S.S., J.H.S., T.K.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; Division of Reproductive Endocrinology and Infertility (M.J.H.), Walter Reed National Military Medical Center, Bethesda, Maryland 20889; Department of Pediatrics (S.S.), Asahikawa Medical University, Asahikawa 078-8510, Japan; Division of Reproductive Sciences and Women's Health Research (J.H.S.), Department of Gynecology and Obstetrics, Johns Hopkins School of Medicine, Baltimore, Maryland 21205; and Department of Experimental Therapeutics (T.K.), Division of Experimental Biology, Sidra Medical and Research Center, Doha 26999, Qatar.
authors.forename: Micah J
authors.initials: MJ
authors.lastname: Hill
authors.affiliation: Program in Reproductive and Adult Endocrinology (M.J.H., S.S., J.H.S., T.K.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; Division of Reproductive Endocrinology and Infertility (M.J.H.), Walter Reed National Military Medical Center, Bethesda, Maryland 20889; Department of Pediatrics (S.S.), Asahikawa Medical University, Asahikawa 078-8510, Japan; Division of Reproductive Sciences and Women's Health Research (J.H.S.), Department of Gynecology and Obstetrics, Johns Hopkins School of Medicine, Baltimore, Maryland 21205; and Department of Experimental Therapeutics (T.K.), Division of Experimental Biology, Sidra Medical and Research Center, Doha 26999, Qatar.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Program in Reproductive and Adult Endocrinology (M.J.H., S.S., J.H.S., T.K.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; Division of Reproductive Endocrinology and Infertility (M.J.H.), Walter Reed National Military Medical Center, Bethesda, Maryland 20889; Department of Pediatrics (S.S.), Asahikawa Medical University, Asahikawa 078-8510, Japan; Division of Reproductive Sciences and Women's Health Research (J.H.S.), Department of Gynecology and Obstetrics, Johns Hopkins School of Medicine, Baltimore, Maryland 21205; and Department of Experimental Therapeutics (T.K.), Division of Experimental Biology, Sidra Medical and Research Center, Doha 26999, Qatar.
authors.forename: James H
authors.initials: JH
authors.lastname: Segars
authors.affiliation: Program in Reproductive and Adult Endocrinology (M.J.H., S.S., J.H.S., T.K.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; Division of Reproductive Endocrinology and Infertility (M.J.H.), Walter Reed National Military Medical Center, Bethesda, Maryland 20889; Department of Pediatrics (S.S.), Asahikawa Medical University, Asahikawa 078-8510, Japan; Division of Reproductive Sciences and Women's Health Research (J.H.S.), Department of Gynecology and Obstetrics, Johns Hopkins School of Medicine, Baltimore, Maryland 21205; and Department of Experimental Therapeutics (T.K.), Division of Experimental Biology, Sidra Medical and Research Center, Doha 26999, Qatar.
authors.forename: Tomoshige
authors.initials: T
authors.lastname: Kino
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D005943:Gluconeogenesis / Q000502:physiology*; D005947:Glucose / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D051379:Mice; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C493245:CRTC2 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D011965:Receptors, Glucocorticoid; D014157:Transcription Factors; D005947:Glucose