Inverse agonist of nuclear receptor ERRγ mediates antidiabetic effect through inhibition of hepatic gluconeogenesis

Don Kyu Kim, Gil Tae Gang, Dongryeol Ryu, Minseob Koh, Yo Na Kim, Su Sung Kim, Jinyoung Park, Yong Hoon Kim, Taebo Sim, In Kyu Lee, Cheol Soo Choi, Seung Bum Park, Chul Ho Lee, Seung-Hoi Koo, Hueng Sik Choi

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36 Citations (Scopus)

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 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 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 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.

Original languageEnglish
Pages (from-to)3093-3102
Number of pages10
JournalDiabetes
Volume62
Issue number9
DOIs
Publication statusPublished - 2013 Sep 1

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Kim, D. K., Gang, G. T., Ryu, D., Koh, M., Kim, Y. N., Kim, S. S., Park, J., Kim, Y. H., Sim, T., Lee, I. K., Choi, C. S., Park, S. B., Lee, C. H., Koo, S-H., & Choi, H. S. (2013). Inverse agonist of nuclear receptor ERRγ mediates antidiabetic effect through inhibition of hepatic gluconeogenesis. Diabetes, 62(9), 3093-3102. https://doi.org/10.2337/db12-0946