Pharmacological Stimulation of NADH Oxidation Ameliorates Obesity and Related Phenotypes in Mice

  1. Jung Hwan Hwang1,
  2. Dong Wook Kim1,
  3. Eun Jin Jo2,
  4. Yong Kyung Kim1,
  5. Young Suk Jo1,
  6. Ji Hoon Park3,
  7. Sang Ku Yoo2,
  8. Myung Kyu Park2,
  9. Tae Hwan Kwak2,
  10. Young Lim Kho4,
  11. Jin Han5,
  12. Hueng-Sik Choi6,
  13. Sang-Hee Lee7,
  14. Jin Man Kim7,
  15. InKyu Lee8,
  16. Taeyoon Kyung9,
  17. Cholsoon Jang9,
  18. Jongkyeong Chung9,
  19. Gi Ryang Kweon3 and
  20. Minho Shong1
  1. 1Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea;
  2. 2Mazence Inc R&D Center, Suwon, Korea;
  3. 3Department of Biochemistry, Chungnam National University School of Medicine, Daejeon, Korea;
  4. 4Department of Environmental Health, Seoul Health College, Sungnam, Korea;
  5. 5Department of Physiology and Biophysics, Inje University College of Medicine, Busan, Korea;
  6. 6Hormone Research Center, Chonnam National University, Kwangju, Korea;
  7. 7Department of Pathology, Chungnam National University School of Medicine, Daejeon, Korea;
  8. 8Section of Endocrinology, Department of Internal Medicine, Kyungpook National University School of Medicine, Junggu, Daegu, Korea;
  9. 9Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
  1. Corresponding author: Minho Shong, minhos{at}cnu.ac.kr, and Gi Ryang Kweon, mitochondria{at}cnu.ac.kr.
  1. J.H.H. and D.W.K. contributed equally to this work.

Abstract

OBJECTIVE Nicotinamide adenine dinucleotides (NAD+ and NADH) play a crucial role in cellular energy metabolism, and a dysregulated NAD+-to-NADH ratio is implicated in metabolic syndrome. However, it is still unknown whether a modulating intracellular NAD+-to-NADH ratio is beneficial in treating metabolic syndrome. We tried to determine whether pharmacological stimulation of NADH oxidation provides therapeutic effects in rodent models of metabolic syndrome.

RESEARCH DESIGN AND METHODS We used β-lapachone (βL), a natural substrate of NADH:quinone oxidoreductase 1 (NQO1), to stimulate NADH oxidation. The βL-induced pharmacological effect on cellular energy metabolism was evaluated in cells derived from NQO1-deficient mice. In vivo therapeutic effects of βL on metabolic syndrome were examined in diet-induced obesity (DIO) and ob/ob mice.

RESULTS NQO1-dependent NADH oxidation by βL strongly provoked mitochondrial fatty acid oxidation in vitro and in vivo. These effects were accompanied by activation of AMP-activated protein kinase and carnitine palmitoyltransferase and suppression of acetyl-coenzyme A (CoA) carboxylase activity. Consistently, systemic βL administration in rodent models of metabolic syndrome dramatically ameliorated their key symptoms such as increased adiposity, glucose intolerance, dyslipidemia, and fatty liver. The treated mice also showed higher expressions of the genes related to mitochondrial energy metabolism (PPARγ coactivator-1α, nuclear respiratory factor-1) and caloric restriction (Sirt1) consistent with the increased mitochondrial biogenesis and energy expenditure.

CONCLUSIONS Pharmacological activation of NADH oxidation by NQO1 resolves obesity and related phenotypes in mice, opening the possibility that it may provide the basis for a new therapy for the treatment of metabolic syndrome.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Received August 28, 2008.
    • Accepted January 1, 2009.
  • 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. 58 no. 4 965-974
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