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

作者：Michèle Guerre-Millo, Christine Rouault, Philippe Poulain, Jocelyne André, Vincent Poitout, Jeffrey M. Peters, Frank J. Gonzalez, Jean‐Charles Fruchart, Gérard Reach, Bart Staels · 发表于：Diabetes · 年份：2001 · DOI：10.2337/diabetes.50.12.2809 · 被引用次数：242 · 研究领域：Peroxisome Proliferator-Activated Receptors、Adipose Tissue and Metabolism、Metabolism, Diabetes, and Cancer

Peroxisome proliferator-activated receptor (PPAR)-alpha controls the expression of genes involved in lipid metabolism. PPAR-alpha furthermore participates to maintain blood glucose during acute metabolic stress, as shown in PPAR-alpha-null mice, which develop severe hypoglycemia when fasted. Here, we assessed a potential role for PPAR-alpha in glucose homeostasis in response to long-term high-fat feeding. When subjected to this nutritional challenge, PPAR-alpha-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-alpha-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-alpha-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-alpha-null mice. In contrast, PPAR-alpha deficiency allowed the twofold rise in adiposity and blood leptin levels elicited by the diet. Thus, the absence of PPAR-alpha dissociates IR from high-fat diet-induced increase in adiposity. The effects of PPAR-alpha deficiency on glucose homeostasis seem...