The hepatic circadian clock plays a key role in the daily regulation of glucose metabolism, but the precise molecular mechanisms that coordinate these two biological processes are not fully understood. In this study, we identify a novel connection between the regulation of RORγ by the clock machinery and the diurnal regulation of glucose metabolic networks. We demonstrate that particularly at daytime, mice deficient in RORγ exhibit improved insulin sensitivity and glucose tolerance due to reduced hepatic gluconeogenesis. This is associated with a reduced peak expression of several glucose metabolic genes critical in the control of gluconeogenesis and glycolysis. Genome-wide cistromic profiling, promoter and mutation analysis support the concept that RORγ regulates the transcription of several glucose metabolic genes directly by binding ROREs in their promoter regulatory region. Similar observations were made in liver-specific RORγ-deficient mice suggesting that the changes in glucose homeostasis were directly related to the loss of hepatic RORγ expression. Altogether, our study shows that RORγ regulates several glucose metabolic genes downstream of the hepatic clock and identifies a novel metabolic function for RORγ in the diurnal regulation of hepatic gluconeogenesis and insulin sensitivity. The inhibition of the activation of several metabolic gene promoters by an RORγ antagonist suggests that antagonists may provide a novel strategy in the management of metabolic diseases, including type 2 diabetes.
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.