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Obesity Studies

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
Diabetes 2007 Jul; 56(7): 1761-1772. https://doi.org/10.2337/db06-1491

Article Figures & Tables

Figures

  • FIG. 1.
    FIG. 1.

    High-fat feeding increased endotoxemia and changed intestinal microbiota. A: Plasma LPS concentration (EU/ml) was assessed every 4 h throughout the day in normal diet (CT; n = 9) (▪) and 4-week high-fat–fed (HF; n = 9) (○) mice. B: Groups of bacteria in the caecal content of mice fed the normal diet (CT; n = 8) or the high-fat diet (HF; n = 8) for 4 weeks. Bacterial numbers are expressed as log10 (bacterial cells per gram caecal content wet weight). *P < 0.05 vs. CT. C: Delta plasma LPS concentration in (EU/ml) in mice before and 30 min after an oral administration of LPS diluted in corn oil (n = 6) (oil-LPS) or in water (n = 6) (H2O-LPS) or an administration of oil alone (n = 6) (oil). *P < 0.05 vs. H2O-LPS. Data are means ± SE.

  • FIG. 2.
    FIG. 2.

    Chronic experimental metabolic endotoxemia induces obesity and diabetes. A: Plasma endotoxin concentration (EU/ml) in WT mice infused with saline (CT; n = 18) or LPS (n = 18) for 4 weeks using subcutaneous osmotic pumps and compared with mice fed a high-fat diet for 4 weeks (HF; n = 18). B: Plasma glucose (mmol/l) following an oral glucose load (3 g/kg) in control (CT; n = 24), LPS (n = 13), or high-fat diet (HF; n = 24) mice. The inset represents the area under curve for each group. *P < 0.05 vs. CT; §LPS vs. CT; #HF vs. LPS. C: Plasma insulin (pmol/l) concentrations 30 min before (−30) and 15 min after (15) an oral glucose load in control (CT; n = 24), LPS (n = 13), or high-fat diet–fed (HF; n = 24) mice. D: Hepatic glucose production and whole-body glucose turnover rates (mg · kg−1 · min−1) in control (CT; n = 5), LPS (n = 5), or high-fat diet–fed (HF; n = 5) mice. E: Body weight (g) before (day 0) and after a 28-day treatment period (day 28) and body weight gain (Δ) in control (CT; n = 26), LPS (n = 21), or high-fat diet–fed (HF; n = 34) mice. F: Visceral and subcutaneous adipose tissue weight (percentage of body weight) in control (CT; n = 26), LPS (n = 21), or high-fat diet–fed (HF; n = 34) mice. G: Liver weight (percentage of body weight) in control (CT; n = 26), LPS (n = 21), or high-fat diet–fed (HF; n = 34) mice. H: Liver triglycerides (μmol/liver) in control (CT; n = 12), LPS (n = 9), or high-fat diet–fed (HF; n = 11) mice. I: Mean energy intake (kcal · day−1 · mouse−1) in control (CT; n = 18), LPS (n = 18), or high-fat diet–fed (HF; n = 18) mice. Data are means ± SE. Data with different superscript letters are significantly different at P < 0.05, according to the post hoc ANOVA statistical analysis.

  • FIG. 3.
    FIG. 3.

    Metabolic endotoxemia triggers the expression of inflammatory factors similarly to high-fat feeding. TNF-α, IL-1, IL-6, and PAI-1 mRNA concentrations (A, E, and I) in liver (B, F, and J), visceral adipose tissue (C, G, and K), subcutaneous adipose tissue (D, H, and L), and muscle in normal diet–fed (n = 8) (□) or high-fat diet–fed (n = 8) (▪) mice for 2 weeks (A–D) and 4 weeks (n = 8) (E–H) and in LPS-infused mice (n = 5) (I–L). Data are means ± SE. *P < 0.05 vs. normal chow–fed mice.

  • FIG. 4.
    FIG. 4.

    CD14 mutant mice are protected against LPS-induced inflammation. mRNA concentrations of IL-6, PAI-1, and IL-1 in adipose tissue 3 h after a saline (control [CT]; n = 6) or an LPS (n = 6) infusion in WT (A) and CD14 mutant (B) mice. *P < 0.05 vs. CT; §P < 0.05 vs. WT. C: Representative Western blot analysis of p-NFk-B and p-IKK-b and p-IKK-a in the liver of mice from the same experiment. Protein Ct corresponds to a loading control of major protein, which cross-reacts nonspecifically with the anti–p-IKK-a antibody.

  • FIG. 5.
    FIG. 5.

    The CD14 null mutation prevents the effect of LPS-induced obesity and diabetes. A: Body weight gain (g) in WT mice infused with saline (WT-CT; n = 13) or LPS (WT-LPS; n = 14) and CD14 mutant mice infused with saline (CD14-CT; n = 13) or LPS (CD14-LPS; n = 12) for 4 weeks using subcutaneous osmotic pumps. B: Visceral and subcutaneous adipose tissue weight (percentage of body weight) in WT-CT (n = 13) (□), WT-LPS (n = 14) (▪), CD14-CT (n = 13) (▒), and CD14-LPS (n = 12) (Embedded Image) mice. C: Plasma glucose concentration (mmol/l) following an intraperitoneal glucose load (1 g/kg) in WT-CT (n = 6) (▪), WT-LPS (n = 6) (▴), CD14-CT (n = 5) (□), and CD14-LPS (n = 6) (•) mice. The inset represents the area under curve of the same groups. D: Plasma insulin (pmol/l) concentration 30 min before (−30) and 30 min after (30) intraperitoneal glucose administration in WT-CT (n = 6) (□), WT-LPS (n = 6) (▪), CD14-CT (n = 5) (Embedded Image), and CD14-LPS (n = 6) (▒) mice. E: Liver weight (percentage of body weight) in WT-CT (n = 13), WT-LPS (n = 13), CD14-CT (n = 12), and CD14-LPS (n = 13) mice. F: Liver triglycerides (μmol/liver) in WT-CT (n = 12), WT-LPS (n = 9), CD14-CT (n = 5), and CD14-LPS (n = 6) mice. Data are means ± SE. Data with different superscript letters are significantly different at P < 0.05, according to the post hoc ANOVA statistical analysis.

  • FIG. 6.

    CD14: the main LPS receptor sets the tone of insulin sensitivity and hepatic steatosis. A: Glucose turnover (mg · kg−1 · min−1) in WT mice or CD14 mutant fed a normal diet (CT) or fed a high-fat diet (HF) for 4 (n = 8) or 24 (n = 8) weeks (wks). B: Body weight gain (g) in WT or CD14 mutant fed a normal diet (CT) for 4 (n = 8) or 24 (n = 8) weeks or fed a high-fat diet (HF) for 4 (n = 8) or 24 (n = 8) weeks. C: Liver weight (percent of body weight) in WT or CD14 mutant mice fed a normal diet (CT) for 4 (n = 8) or 24 (n = 8) weeks or fed a high-fat diet (HF) for 4 (n = 8) or 24 (n = 8) weeks. D: Liver triglycerides (μmol/liver) in WT or CD14 mutant mice fed a normal diet (CT) for 4 (n = 6) or 24 (n = 5) weeks or fed a high-fat diet (HF) for 4 (n = 5) or 24 (n = 5) weeks. Data are means ± SE. *P < 0.05 vs. CT; §P < 0.05 vs. WT. E: Representative oil red O liver staining in 4-week–treated mice. F (see next page): Plasma glucose following an intraperitoneal glucose load (1 g/kg) in WT mice fed a normal diet (WT-CT; n = 8) or a high-fat diet (WT-HF; n = 8) for 24 weeks and CD14 mutant mice fed a normal diet (CD14-CT; n = 8) or fed a high-fat diet (CD14-HF; n = 8). The inset represents the area under curve of the same groups. G (see next page): Fasting plasma insulin (pmol/l) in WT or CD14 mutant mice fed a normal diet (CT) for 4 (n = 6) or 24 (n = 5) weeks or fed a high-fat diet (HF) for 4 (n = 5) or 24 (n = 5) weeks. Data are means ± SE. *P < 0.05 vs. CT; §P < 0.05 vs. WT. Data with different superscript letters are significantly different at P < 0.05, according to the post hoc ANOVA statistical analysis.

  • FIG. 7.
    FIG. 7.

    CD14 mutant mice resist high-fat diet–induced glucose intolerance, inflammation, and increased visceral fat mass. A: Plasma glucose (mmol/l) following an intraperitoneal glucose load (1 g/kg) in WT mice fed a normal diet (WT-CT; n = 6) (▪) or a high-fat diet (WT-HF; n = 6) (▴) for 4 weeks and CD14 mutant mice fed a normal diet (CD14-CT; n = 5) (•) or fed a high-fat diet (CD14-HF; n = 5) (□). The inset represents the area under curve of the same groups. B: Plasma insulin concentration (pmol/l) 30 min before (−30) and 30 min after (30) intraperitoneal glucose administration in WT-CT (n = 6) (□), WT-HF (n = 6) (▪), CD14-CT (n = 5) ( ▒), and CD14-HF (n = 5) (Embedded Image) mice. C: Visceral and subcutaneous adipose tissue weight (percent of body weight) in WT-CT (n = 6) (□), WT-HF (n = 6) (▪), CD14-CT (n = 5) (▒), and CD14-HF (n = 5) (Embedded Image) mice. Adipose tissue (D) and liver (E) mRNA concentrations of TNF-α, IL-1, IL-6, and PAI-1 in WT-CT (n = 6) (□), WT-HF (n = 6) (▪), CD14-CT (n = 5) (▒), and CD14-HF (n = 5) (Embedded Image) mice. Data are means ± SE. Data with different superscript letters are significantly different at P < 0.05, according to the post hoc ANOVA statistical analysis.

  • FIG. 8.

    Metabolic endotoxemia impairs adipocyte morphology. A: Adipocyte size distribution (%) in WT mice fed a normal diet (WT-CT; n = 765) (□) or a high-fat diet (WT-HF; n = 661) (▪) for 4 weeks or CD14 mutant mice fed a normal diet (CD14-CT; n = 1,032) ( ▒) or a high-fat diet (CD14-HF; n = 729) (Embedded Image) for 4 weeks. B: Adipocyte size distribution (%) in WT mice infused with saline (WT-CT; n = 765) (□) or LPS (WT-LPS; n = 750) (▪) and CD14 mutant mice infused with saline (CD14-CT; n = 1,032) (▒) or LPS (CD14-LPS; n = 585) (Embedded Image) for 4 weeks using subcutaneous osmotic pumps. C: Adipocyte mean area (μm2) in WT-CT (n = 765), WT-HF (n = 661), WT-LPS (n = 750), CD14-CT (n = 1,032), CD14-HF (n = 729), or CD14-LPS (n = 585) mice. D: Representative adipose tissue staining in 4-week–treated mice. E: F4/80-positive cells (+ cells/total cells) of all above groups. Data are means ± SE. Data with different superscript letters are significantly different at P < 0.05, according to the post hoc ANOVA statistical analysis.

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July 2007, 56(7)
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Metabolic Endotoxemia Initiates Obesity and Insulin Resistance
Patrice D. Cani, Jacques Amar, Miguel Angel Iglesias, Marjorie Poggi, Claude Knauf, Delphine Bastelica, Audrey M. Neyrinck, Francesca Fava, Kieran M. Tuohy, Chantal Chabo, Aurélie Waget, Evelyne Delmée, Béatrice Cousin, Thierry Sulpice, Bernard Chamontin, Jean Ferrières, Jean-François Tanti, Glenn R. Gibson, Louis Casteilla, Nathalie M. Delzenne, Marie Christine Alessi, Rémy Burcelin
Diabetes Jul 2007, 56 (7) 1761-1772; DOI: 10.2337/db06-1491
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