Abstract
Glucose homeostasis is tightly controlled by hormonal regulation of hepatic glucose production. Dysregulation of this system is often associated with insulin resistance and diabetes, resulting in hyperglycemia in mammals. Here, we show that the orphan nuclear receptor estrogen-related receptor γ (ERRγ) is a novel downstream mediator of glucagon action in hepatic gluconeogenesis and demonstrate a beneficial impact of the inverse agonist GSK5182. Hepatic ERRγ expression was increased by fasting-dependent activation of the cAMP-response element-binding protein-CRTC2 pathway. Overexpression of ERRγ induced Pck1 and G6PC gene expression and glucose production in primary hepatocytes, whereas abolition of ERRγ gene expression attenuated forskolin-mediated induction of gluconeogenic gene expression. Deletion and mutation analyses of the Pck1 promoter showed that ERRγ directly regulates the Pck1 gene transcription via ERR response elements of the Pck1 promoter as confirmed by ChIP assay and in vivo imaging analysis. We also demonstrate that GSK5182, an inverse agonist of ERRγ, specifically inhibits the transcriptional activity of ERRγ in a PGC-1α dependent manner. Finally, the ERRγ inverse agonist ameliorated hyperglycemia through inhibition of hepatic gluconeogenesis in db/db mice. Control of hepatic glucose production by an ERRγ-specific inverse agonist is a new potential therapeutic approach for the treatment of type 2 diabetes.
Highlights
Dysregulation of glucose homeostasis is often associated with insulin resistance and diabetes
We identified the orphan nuclear receptor ERR␥ as a novel alternative downstream mediator of cAMPCREB in hepatic glucose metabolism (Fig. 7), which is evidenced by the results showing that FSK-mediated induction ofPck1 and G6PC mRNA expression was faster than the induction of ERR␥ mRNA expression in vivo and in vitro
These results are further supported by the chromatin immunoprecipitation (ChIP) assay showing that ERR␥ occupancy was weakly increased by 1-h stimulation with FSK, and the occupancy on Pck1 ERR response element (ERRE) was strongly enhanced by 6-h treatment with FSK
Summary
Dysregulation of glucose homeostasis is often associated with insulin resistance and diabetes. Glucose homeostasis is tightly controlled by hormonal regulation of hepatic glucose production Dysregulation of this system is often associated with insulin resistance and diabetes, resulting in hyperglycemia in mammals. We show that the orphan nuclear receptor estrogen-related receptor ␥ (ERR␥) is a novel downstream mediator of glucagon action in hepatic gluconeogenesis and demonstrate a beneficial impact of the inverse agonist GSK5182. Control of hepatic glucose production by an ERR␥-specific inverse agonist is a new potential therapeutic approach for the treatment of type 2 diabetes. We have demonstrated that orphan nuclear receptor ERR␥ is a novel transcriptional regulator of hepatic gluconeogenesis, and its inverse agonist could ameliorate hyperglycemia in mouse models of type 2 diabetes
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