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

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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

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