title: Inverse agonist of nuclear receptor ERRγ mediates antidiabetic effect through inhibition of hepatic gluconeogenesis.
abstract: 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 ERRγ is a major contributor to hyperglycemia under diabetic conditions by controlling hepatic glucose production. Hepatic ERRγ 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 ERRγ 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 long-term studies of the antidiabetic effects of GSK5182, the ERRγ-specific 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.
authors.affiliation: National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Don-Kyu
authors.initials: DK
authors.lastname: Kim
authors.forename: Gil-Tae
authors.initials: GT
authors.lastname: Gang
authors.forename: Dongryeol
authors.initials: D
authors.lastname: Ryu
authors.forename: Minseob
authors.initials: M
authors.lastname: Koh
authors.forename: Yo-Na
authors.initials: YN
authors.lastname: Kim
authors.forename: Su Sung
authors.initials: SS
authors.lastname: Kim
authors.forename: Jinyoung
authors.initials: J
authors.lastname: Park
authors.forename: Yong-Hoon
authors.initials: YH
authors.lastname: Kim
authors.forename: Taebo
authors.initials: T
authors.lastname: Sim
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
authors.forename: Cheol Soo
authors.initials: CS
authors.lastname: Choi
authors.forename: Seung Bum
authors.initials: SB
authors.lastname: Park
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Lee
authors.forename: Seung-Hoi
authors.initials: SH
authors.lastname: Koo
authors.forename: Hueng-Sik
authors.initials: HS
authors.lastname: Choi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D005943:Gluconeogenesis / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016133:Polymerase Chain Reaction; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000819:agonists* / Q000378:metabolism*; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: C490916:Esrrg protein, mouse; C583041:GSK5182; D007004:Hypoglycemic Agents; D011960:Receptors, Estrogen; D013629:Tamoxifen