Retinoic acid-related orphan receptor ? (ROR?): a novel participant in the diurnal regulation of hepatic gluconeogenesis and insulin sensitivity.

ABSTRACT: 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 ROR? by the clock machinery and the diurnal regulation of glucose metabolic networks. We demonstrate that particularly at daytime, mice deficient in ROR? 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 ROR? regulates the transcription of several glucose metabolic genes directly by binding ROREs in their promoter regulatory region. Similar observations were made in liver-specific ROR?-deficient mice suggesting that the changes in glucose homeostasis were directly related to the loss of hepatic ROR? expression. Altogether, our study shows that ROR? regulates several glucose metabolic genes downstream of the hepatic clock and identifies a novel metabolic function for ROR? in the diurnal regulation of hepatic gluconeogenesis and insulin sensitivity. The inhibition of the activation of several metabolic gene promoters by an ROR? antagonist suggests that antagonists may provide a novel strategy in the management of metabolic diseases, including type 2 diabetes.

SUBMITTER: Takeda Y 

PROVIDER: S-EPMC4022472 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature