Retinoic Acid-Related Orphan Receptor γ (RORγ): 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 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.

Antiobesity Effect of a Small Molecule Repressor of RORγ

“…Within the NR1F subfamily of NRs, RORgt has garnered much attention due to its role in T H 17 cells. However, its contribution to obesity and insulin resistance has been recently demonstrated (Meissburger et al, 2011;Takeda et al, 2014). The discovery that the potent LXR agonist T0901317 [N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-benzenesulfonamide] also functioned as an inverse agonist for RORa and RORg and SR1555 .…”

Isoflavones enhance interleukin-17 gene expression via retinoic acid receptor-related orphan receptors α and γ

“…The retinoic acid receptor-related orphan receptors, RORα-γ (NR1F1-3), are members of the nuclear receptor superfamily and function as ligand-dependent transcription factors that are involved in the regulation of a wide range of physiological processes, including immune response, lipid/glucose homeostasis, and circadian rhythm (Jetten, 2009; Jetten et al, 2013; Takeda et al, 2014a,b). They are considered to be orphan receptors because their endogenous ligands have not yet been agreed upon definitively, and they have been identified with distinct tissue distributions and biological activities (Jetten, 2009).…”

The hepatic circadian clock fine-tunes the lipogenic response to feeding through RORα/γ

“…Only RORα and RORγ are highly expressed in the liver, while RORβ is expressed mainly in the central nervous system (Forman et al 1994;Andre et al 1998;Takeda et al 2012). Studies of total body knockout mice reported that both RORα-and RORγ-deficient mice exhibited improved insulin sensitivity and glucose tolerance with decreased hepatic gluconeogenesis (Takeda et al 2014a;Kadiri et al 2015). RORα-deficient mice, which suffer from severe cerebellar defects and display a staggerer phenotype (Sidman et al 1962;Dussault et al 1998;Steinmayr et al 1998), also exhibited lower total body fat and were resistant to age-induced white adipose tissue (WAT) and brown adipose tissue (BAT) hypertrophy (Kang et al 2011).…”