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High-Throughput Assay for Modulators of Mitochondrial Membrane Potential Identifies a Novel Compound With Beneficial Effects on db/db Mice

  1. Bei-Ying Qiu1,
  2. Nigel Turner2,3,
  3. Yuan-Yuan Li1,
  4. Min Gu1,
  5. Meng-Wei Huang4,
  6. Fang Wu1,
  7. Tao Pang1,
  8. Fa-Jun Nan1,
  9. Ji-Ming Ye2,5,
  10. Jing-Ya Li1 and
  11. Jia Li1
  1. 1National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China;
  2. 2Diabetes and Obesity Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, Australia;
  3. 3St. Vincent's Hospital Clinical School, University of New South Wales, Sydney, New South Wales, Australia;
  4. 4Roche R&D Center (China), Shanghai, China;
  5. 5School of Medical Sciences, University of New South Wales, Sydney, New South Wales, Australia.
  1. Corresponding authors: Jia Li, jli{at}mail.shcnc.ac.cn, and Jing-Ya Li, jyli{at}mail.shcnc.ac.cn.

Abstract

OBJECTIVE Recently, several drugs have been shown to exert beneficial effects for metabolic syndrome through mild regulation of mitochondrial function. Hence, we explored a strategy of targeting mitochondrial function to improve glucose and lipid metabolism.

RESEARCH DESIGN AND METHODS Mitochondrial membrane potential (Δψm) is a marker of mitochondrial function; therefore, we set up a high-throughput screening assay of Δψm in L6 myotubes. The effects of a selected lead compound were investigated in vitro and in vivo in relation to metabolic syndrome.

RESULTS A novel small-molecule compound, C1, was identified through this high-throughput screening. C1 depolarized Δψm in L6 myotubes without cytotoxicity and led to increased cellular AMP-to-ATP ratio, activation of AMP-activated protein kinase (AMPK), and enhanced glucose uptake. It also stimulated the AMPK pathway in HepG2 cells, leading to decreased lipid content. Intriguingly, C1 inhibited respiration in L6 myotubes but did not affect respiration in isolated muscle mitochondria, suggesting that it may depolarize Δψm indirectly by affecting the supply of electron donors. Acute administration of C1 in C57BL/6J mice markedly increased fat oxidation and the phosphorylation of AMPK and acetyl-CoA carboxylase in the liver. In diabetic db/db mice, chronic administration of C1 significantly reduced hyperglycemia, plasma fatty acids, glucose intolerance, and the mRNA levels of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase in the liver.

CONCLUSIONS Our results demonstrate a novel small molecule that mildly depolarizes Δψm and is able to improve glucose and lipid metabolism to exert beneficial effects for metabolic syndrome. These findings suggest that compounds regulating mitochondrial function may have therapeutic potential for type 2 diabetes.

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 February 16, 2009.
    • Accepted September 27, 2009.
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  1. Diabetes vol. 59 no. 1 256-265
  1. Online-Only Appendix
  2. All Versions of this Article:
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