| First Author | Takeda Y | Year | 2014 |
| Journal | PLoS Genet | Volume | 10 |
| Issue | 5 | Pages | e1004331 |
| PubMed ID | 24831725 | Mgi Jnum | J:226654 |
| Mgi Id | MGI:5698026 | Doi | 10.1371/journal.pgen.1004331 |
| Citation | Takeda Y, et al. (2014) Retinoic acid-related orphan receptor gamma (RORgamma): a novel participant in the diurnal regulation of hepatic gluconeogenesis and insulin sensitivity. PLoS Genet 10(5):e1004331 |
| abstractText | 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 RORgamma by the clock machinery and the diurnal regulation of glucose metabolic networks. We demonstrate that particularly at daytime, mice deficient in RORgamma 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 RORgamma regulates the transcription of several glucose metabolic genes directly by binding ROREs in their promoter regulatory region. Similar observations were made in liver-specific RORgamma-deficient mice suggesting that the changes in glucose homeostasis were directly related to the loss of hepatic RORgamma expression. Altogether, our study shows that RORgamma regulates several glucose metabolic genes downstream of the hepatic clock and identifies a novel metabolic function for RORgamma in the diurnal regulation of hepatic gluconeogenesis and insulin sensitivity. The inhibition of the activation of several metabolic gene promoters by an RORgamma antagonist suggests that antagonists may provide a novel strategy in the management of metabolic diseases, including type 2 diabetes. |
