Retinoic Acid-Related Orphan Receptor γ (RORγ): A Novel Participant in the Diurnal Regulation of Hepatic Gluconeogenesis and Insulin Sensitivity
Figure 7
Liver-specific RORγ deficient mice exhibit improved insulin sensitivity and reduced gluconeogenesis.
(A) RORγ expression in liver and kidney collected from RORγfx/fxAlb-Cre+ and -Alb-Cre− mice at ZT8 and ZT20 (n = 4–5). GTT (B), ITT (C), and PTT (D) were examined during ZT4–6 in RORγfx/fxAlb-Cre+ and -Alb-Cre− mice fed with a HFD (n = 7–11). (E) Serum insulin levels were measured at ZT4 (n = 8) and ZT16 (n = 15–16) in RORγfx/fxAlb-Cre+ and -Alb-Cre− mice on a HFD. Hepatic glycogen was measured at ZT0. Data represent mean ±SEM, * P<0.05, ** P<0.01 by ANOVA. (F) The expression of a series of glucose metabolic genes was analyzed in the liver collected at ZT8 or ZT20 (n = 4–5). Data represent mean ±SD, * P<0.05, ** P<0.01, *** P<0.001 by ANOVA. (G) RORγ coordinates the regulation of circadian rhythm, hepatic glucose metabolism, and insulin sensitivity. Genome-wide cistromic profiling and promoter analysis revealed that RORγ is targeting and regulating a number of metabolic genes critical in the control of glycolysis, gluconeogenesis and glycogenesis pathways. The loss of RORγ in hepatocytes reduces the expression of these genes and hepatic gluconeogenesis in a diurnal time-dependent manner that results in improved insulin sensitivity. Due to reduced hepatic glucose production, RORγ−/− mice may require less insulin than WT mice to maintain blood glucose levels. A decrease in glucose uptake due to lower insulin levels as well as reduced Gys2 expression may in part be responsible for the reduced accumulation of liver glycogen. Our study supports the model that the circadian regulation of several glucose metabolic genes by RORγ in liver is linked to its circadian control of gluconeogenesis, insulin sensitivity, and glucose tolerance and is consistent with the idea that RORγ functions as a positive regulator of gluconeogenesis and is positively linked to increased risk for type 2 diabetes.