Peroxisome proliferator-activated receptor-alpha deficiency protects aged mice from insulin resistance induced by high-fat diet

Abstract

Background/Aims: Insulin resistance is a central feature of the metabolic syndrome and progressively increases with age, resulting in excessively high incidence of type II diabetes in the elderly population. Peroxisome proliferator-activated receptor-alpha (PPAR alpha) is widely expressed in insulin target tissues, including those of the liver, kidney, and muscle, where it mediates expression of genes promoting fatty acid beta-oxidation. The aim of this study was to evaluate the potential role of PPAR alpha in insulin resistance in aging mice induced by a high-fat diet. Methods: We used male PPAR alpha knockout (KO) mice and wild-type (WT) littermates that were 18 months old. Animals were fed with a high-fat diet (HFD) for 4 weeks, and metabolic parameters associated with insulin sensitivity were assessed. Results: Following HFD treatment, WT mice showed more severe insulin resistance than did mice lacking the PPAR alpha gene, as assessed by both the glucose tolerance test (GTT) and insulin tolerance test (ITT). In addition, WT mice exhibited significantly higher HOMA-IR, plasma total cholesterol levels and urinary albumin-creatinine ratio but less liver weight than did PPAR alpha KO mice. Conclusion: These data suggest that PPAR alpha gene deficiency may protect aged mice from developing insulin resistance and albuminuria induced by a HFD. Copyright (c) 2007 S. Karger AG, Basel.