Inverse Agonist of Nuclear Receptor ERRγ Mediates Antidiabetic Effect Through Inhibition of Hepatic Gluconeogenesis

  1. Hueng-Sik Choi1,10
  1. 1National 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
  2. 2Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea
  3. 3Department of Life Sciences, Korea University, Seoul, Republic of Korea
  4. 4Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul, Korea
  5. 5Korea Mouse Metabolic Phenotyping Center, Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Incheon, Republic of Korea
  6. 6Chemical Kinomics Research Center, Future Convergence Research Division, Korean Institute of Science and Technology, Seoul, Republic of Korea
  7. 7Department of Internal Medicine and World Class University Program, Kyungpook National University School of Medicine, Daegu, Republic of Korea
  8. 8Gil Medical Center, Gachon University of Medicine and Science, Incheon, Republic of Korea
  9. 9Department of Biophysics and Chemical Biology, College of Natural Sciences, Seoul National University, Seoul, Korea
  10. 10Research Institute of Medical Sciences, Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju, Republic of Korea.
  1. Corresponding authors: Hueng-Sik Choi, hsc{at}chonnam.ac.kr; Seung-Hoi Koo, koohoi{at}korea.ac.kr; Chul-Ho Lee, chullee{at}kribb.re.kr; and Seung Bum Park, sbpark{at}snu.ac.kr.
  1. D.-K.K., G.-T.G., and D.R. contributed equally to this work.

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.

Footnotes

  • Received July 16, 2012.
  • Accepted June 10, 2013.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

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  1. Diabetes vol. 62 no. 9 3093-3102
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