Inverse Agonist of Nuclear Receptor ERRγ Mediates Antidiabetic Effect Through Inhibition of Hepatic Gluconeogenesis
- Inverse Agonist of Nuclear Receptor ERRγ Mediates Antidiabetic Effect Through Inhibition of Hepatic Gluconeogenesis
- 김돈규; 강길태; 류동렬; 고민섭; 김요나; 김서성; 박진영; 김용훈; 심태보; 이인규; 최철수; 박승범; 이철호; 구승회; 최흥식
- diabetes; ERR
- Issue Date
- VOL 62, NO 9, 3093-3102
- Type 2 diabetes mellitus (T2DM) is a progressive metabolic
disorder with diverse pathological manifestations and is often
associated with abnormal regulation of hepatic glucose production.
Many nuclear receptors known to control the hepatic
gluconeogenic program are potential targets for the treatment of
T2DM and its complications. Nevertheless, the therapeutic
potential of the estrogen-related receptor γ (ERRγ) in T2DM
remains unknown. In this study, we show that the nuclear receptor
ERRg is a major contributor to hyperglycemia under diabetic
conditions by controlling hepatic glucose production.
Hepatic ERRg expression induced by fasting and diabetic conditions
resulted in elevated levels of gluconeogenic gene expression
and blood glucose in wild-type mice. Conversely, ablation of
hepatic ERRg gene expression reduced the expression of gluconeogenic
genes and normalized blood glucose levels in mouse
models of T2DM: db/db and diet-induced obesity (DIO) mice. In
addition, a hyperinsulinemic-euglycemic clamp study and longterm
studies of the antidiabetic effects of GSK5182, the ERRgspecific
inverse agonist, in db/db and DIO mice demonstrated that
GSK5182 normalizes hyperglycemia mainly through inhibition of
hepatic glucose production. Our findings suggest that the ability
of GSK5182 to control hepatic glucose production can be used as
a novel therapeutic approach for the treatment of T2DM.
- Appears in Collections:
- KIST Publication > Article
- Files in This Item:
There are no files associated with this item.
- RIS (EndNote)
- XLS (Excel)
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.