Metabolic Endotoxemia Initiates Obesity and Insulin Resistance

  1. Patrice D. Cani12,
  2. Jacques Amar3,
  3. Miguel Angel Iglesias1,
  4. Marjorie Poggi4,
  5. Claude Knauf1,
  6. Delphine Bastelica4,
  7. Audrey M. Neyrinck2,
  8. Francesca Fava5,
  9. Kieran M. Tuohy5,
  10. Chantal Chabo1,
  11. Aurélie Waget1,
  12. Evelyne Delmée2,
  13. Béatrice Cousin6,
  14. Thierry Sulpice7,
  15. Bernard Chamontin3,
  16. Jean Ferrières3,
  17. Jean-François Tanti8,
  18. Glenn R. Gibson5,
  19. Louis Casteilla6,
  20. Nathalie M. Delzenne2,
  21. Marie Christine Alessi4 and
  22. Rémy Burcelin1
  1. 1Institute of Molecular Medicine, I2MR Toulouse, France
  2. 2Unité Pharmacokinetics, Metabolism, Nutrition, and Toxicology-73/69, Université catholique de Louvain, Brussels, Belgium
  3. 3Institut National de la Santé et de la Recherche Médicale (INSERM) 558, Toulouse, France
  4. 4INSERM U 626, Marseille, France
  5. 5Food Microbial Sciences Unit, Department of Food Biosciences, University of Reading, Reading, U.K
  6. 6Unité Mixte de Recherche 5241, Centre National de la Recherche Scientifique, Université Paul Sabatier, Toulouse, France
  7. 7Physiogenex S.A.S., Labège Innopole, France
  8. 8INSERM U 568, Nice, France
  1. Address correspondence and reprint requests to Rémy Burcelin, I2MR U858, IFR 31, Hôpital Rangueil, BP 84225, Toulouse 31432 Cedex 4, France. E-mail: burcelin{at}toulouse.inserm.fr

Abstract

Diabetes and obesity are two metabolic diseases characterized by insulin resistance and a low-grade inflammation. Seeking an inflammatory factor causative of the onset of insulin resistance, obesity, and diabetes, we have identified bacterial lipopolysaccharide (LPS) as a triggering factor. We found that normal endotoxemia increased or decreased during the fed or fasted state, respectively, on a nutritional basis and that a 4-week high-fat diet chronically increased plasma LPS concentration two to three times, a threshold that we have defined as metabolic endotoxemia. Importantly, a high-fat diet increased the proportion of an LPS-containing microbiota in the gut. When metabolic endotoxemia was induced for 4 weeks in mice through continuous subcutaneous infusion of LPS, fasted glycemia and insulinemia and whole-body, liver, and adipose tissue weight gain were increased to a similar extent as in high-fat–fed mice. In addition, adipose tissue F4/80-positive cells and markers of inflammation, and liver triglyceride content, were increased. Furthermore, liver, but not whole-body, insulin resistance was detected in LPS-infused mice. CD14 mutant mice resisted most of the LPS and high-fat diet–induced features of metabolic diseases. This new finding demonstrates that metabolic endotoxemia dysregulates the inflammatory tone and triggers body weight gain and diabetes. We conclude that the LPS/CD14 system sets the tone of insulin sensitivity and the onset of diabetes and obesity. Lowering plasma LPS concentration could be a potent strategy for the control of metabolic diseases.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 24 April 2007. DOI: 10.2337/db06-1491.

  • P.D.C., J.A., and M.A.I. contributed equally to this article.

  • 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.

    • Accepted April 13, 2007.
    • Received October 24, 2006.
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  1. Diabetes vol. 56 no. 7 1761-1772
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