PPAR-α–Null Mice Are Protected From High-Fat Diet–Induced Insulin Resistance

  1. Michèle Guerre-Millo1,
  2. Christine Rouault2,
  3. Philippe Poulain3,
  4. Jocelyne André1,
  5. Vincent Poitout4,
  6. Jeffrey M. Peters5,
  7. Frank J. Gonzalez5,
  8. Jean-Charles Fruchart3,
  9. Gérard Reach2 and
  10. Bart Staels3
  1. 1Unit 465, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
  2. 2Unit 341, INSERM, Hôtel-Dieu, Paris, France
  3. 3Unit 545, INSERM, Département d’Athérosclérose, Institut Pasteur de Lille and Faculté de Pharmacie, Université de Lille II, Lille, France
  4. 4Pacific Northwest Research Institute and the Department of Medicine, University of Washington, Seattle, Washington
  5. 5Laboratory of Metabolism, National Cancer Institute, Bethesda, Maryland


    Peroxisome proliferator–activated receptor (PPAR)-α controls the expression of genes involved in lipid metabolism. PPAR-α furthermore participates to maintain blood glucose during acute metabolic stress, as shown in PPAR-α–null mice, which develop severe hypoglycemia when fasted. Here, we assessed a potential role for PPAR-α in glucose homeostasis in response to long-term high-fat feeding. When subjected to this nutritional challenge, PPAR-α–null mice remained normoglycemic and normoinsulinemic, whereas wild-type mice became hyperinsulinemic (190%; P < 0.05) and slightly hyperglycemic (120%; NS). Insulin tolerance tests (ITTs) and glucose tolerance tests (GTTs) were performed to evaluate insulin resistance (IR). Under standard diet, the response to both tests was similar in wild-type and PPAR-α–null mice. Under high-fat diet, however, the efficiency of insulin in ITT was reduced and the amount of hyperglycemia in GTT was increased only in wild-type and not in PPAR-α–null mice. The IR index, calculated as the product of the areas under glucose and insulin curves in GTT, increased fourfold in high-fat–fed wild-type mice, whereas it remained unchanged in PPAR-α–null mice. In contrast, PPAR-α deficiency allowed the twofold rise in adiposity and blood leptin levels elicited by the diet. Thus, the absence of PPAR-α dissociates IR from high-fat diet–induced increase in adiposity. The effects of PPAR-α deficiency on glucose homeostasis seem not to occur via the pancreas, because glucose-stimulated insulin secretion of islets was not influenced by the PPAR-α genotype. These data suggest that PPAR-α plays a role for the development of IR in response to a Western-type high-fat diet.


    • Address correspondence and reprint requests to Bart Staels, Institut Pasteur de Lille, F-59019 Lille, France. E-mail: bart.staels{at}pasteur-lille.fr.

      Received for publication 20 April 2001 and accepted in revised form 13 September 2001.

      J.M.P. is currently affiliated with the Department of Veterinary Science and Center for Molecular Toxicology, Pennsylvania State University, Pennsylvania.

      AUC, area under the curve; G6Pase, glucose-6-phosphatase; GK, glucokinase; GTT, glucose tolerance test; 11β-HSD-1, 11β-hydroxysteroid dehydrogenase type 1; IR, insulin resistance; ITT, insulin tolerance test; PPAR, peroxisome proliferator–activated receptor.

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