Endothelial Nitric Oxide Synthase (eNOS) Knockout Mice Have Defective Mitochondrial β-Oxidation

  1. Eric Le Gouill1,
  2. Maria Jimenez2,
  3. Christophe Binnert3,
  4. Pierre-Yves Jayet4,
  5. Sebastien Thalmann4,
  6. Pascal Nicod4,
  7. Urs Scherrer4 and
  8. Peter Vollenweider4
  1. 1Department of Cellular Biology and Morphology, University of Lausanne, Switzerland
  2. 2Department of Biochemistry and Physiology, CMU, University of Geneva, Geneva, Switzerland
  3. 3Institute of Physiology, University of Lausanne, Lausanne, Switzerland
  4. 4Department of Internal Medicine and the Botnar Center for Clinical Research, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
  1. Address correspondence and reprint requests to Peter Vollenweider, MD, Department of Internal Medicine, BH 10.624, Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland. E-mail: peter.vollenweider{at}chuv.ch

Abstract

OBJECTIVE— Recent observations indicate that the delivery of nitric oxide by endothelial nitric oxide synthase (eNOS) is not only critical for metabolic homeostasis, but could also be important for mitochondrial biogenesis, a key organelle for free fatty acid (FFA) oxidation and energy production. Because mice deficient for the gene of eNOS (eNOS−/−) have increased triglycerides and FFA levels, in addition to hypertension and insulin resistance, we hypothesized that these knockout mice may have decreased energy expenditure and defective β-oxidation.

RESEARCH DESIGN AND METHODS— Several markers of mitochondrial activity were assessed in C57BL/6J wild-type or eNOS−/− mice including the energy expenditure and oxygen consumption by indirect calorimetry, in vitro β-oxidation in isolated mitochondria from skeletal muscle, and expression of genes involved in fatty acid oxidation.

RESULTS— eNOS−/− mice had markedly lower energy expenditure (−10%, P < 0.05) and oxygen consumption (−15%, P < 0.05) than control mice. This was associated with a roughly 30% decrease of the mitochondria content (P < 0.05) and, most importantly, with mitochondrial dysfunction, as evidenced by a markedly lower β-oxidation of subsarcolemmal mitochondria in skeletal muscle (−30%, P < 0.05). Finally, impaired mitochondrial β-oxidation was associated with a significant increase of the intramyocellular lipid content (30%, P < 0.05) in gastrocnemius muscle.

CONCLUSIONS— These data indicate that elevated FFA and triglyceride in eNOS−/− mice result in defective mitochondrial β-oxidation in muscle cells.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 11 September 2007. DOI: 10.2337/db06-1228.

    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 September 2, 2006.
    • Accepted August 2, 2007.
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  1. Diabetes vol. 56 no. 11 2690-2696
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