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

¹ Unit 465, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France
² Unit 341, INSERM, Hôtel-Dieu, Paris, France
³ Unit 545, INSERM, Département d’Athérosclérose, Institut Pasteur de Lille and Faculté de Pharmacie, Université de Lille II, Lille, France
⁴ Pacific Northwest Research Institute and the Department of Medicine, University of Washington, Seattle, Washington
⁵ Laboratory of Metabolism, National Cancer Institute, Bethesda, Maryland

Peroxisome proliferator–activated receptor (PPAR)- controls the expression of genes involved in lipid metabolism. PPAR- furthermore participates to maintain blood glucose during acute metabolic stress, as shown in PPAR-–null mice, which develop severe hypoglycemia when fasted. Here, we assessed a potential role for PPAR- in glucose homeostasis in response to long-term high-fat feeding. When subjected to this nutritional challenge, PPAR-–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-–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-–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-–null mice. In contrast, PPAR- deficiency allowed the twofold rise in adiposity and blood leptin levels elicited by the diet. Thus, the absence of PPAR- dissociates IR from high-fat diet–induced increase in adiposity. The effects of PPAR- deficiency on glucose homeostasis seem not to occur via the pancreas, because glucose-stimulated insulin secretion of islets was not influenced by the PPAR- genotype. These data suggest that PPAR- plays a role for the development of IR in response to a Western-type high-fat diet.

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