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-α (PPARα) is widely expressed in insulin target tissues, including those of the liver, kidney, and muscle, where it mediates expression of genes promoting fatty acid β-oxidation. The aim of this study was to evaluate the potential role of PPARα in insulin resistance in aging mice induced by a high-fat diet. Methods: We used male PPARα 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 PPARα 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 PPARα KO mice. Conclusion: These data suggest that PPARα gene deficiency may protect aged mice from developing insulin resistance and albuminuria induced by a HFD.

Midlife gene expressions identify modulators of aging through dietary interventions

“…Although speculative, this idea is supported by both the experimental data in worms and flies and the highly negative correlation of peroxisome gene expression with lifespan under different dietary regimens in mice. This finding is also supported by the suppression of many aging-related metabolic phenotypes, including insulin resistance, in PPARα KO mice when fed a HF diet (33). Intuitively, one might think that the negative correlation of PEX genes expression with lifespan would result from induction of these genes in response to a HF diet, because fatty acids are activators for PPARα; however, in reality, it could be mostly attributed to the strong suppression of these genes under CR (both LF+CR and HF+CR) (Fig.…”

Metabolic abnormalities of the heart in type II diabetes

“…26 Increased PPAR-α activity is evident in rodent models of DiCM, and hearts from PPAR-α knock-out mice do not remodel when rendered insulin resistant. 44 In patients with T2DM, a twofold increase in cardiac FA oxidation has been described, 45 and aberrant FA metabolism has been correlated to adverse cardiac changes (Figure 3).…”

Taking Diabetes to Heart—Deregulation of Myocardial Lipid Metabolism in Diabetic Cardiomyopathy

“…An increase in PPARα expression was reported in almost all rodent models of diabetic cardiomyopathy, including streptozotocin‐induced T1DM, 108–109 Zucker diabetic fatty rats, 110 and ob/ob and db/db mice, 111 whereas deletion of the PPARα gene protected mice against high‐fat‐diet‐induced diabetes. 112–113 The key role of PPARα induction in the development of diabetic cardiomyopathy is exemplified by the study by Finck et al, 48 in which cardiac PPARα overexpression in the mouse produced a phenotype that mimicked diabetic cardiomyopathy in the absence of systemic insulin resistance, hyperglycemia, or dyslipidemia. Importantly, the hearts from PPARα transgenic mice exhibited increased rates of palmitate uptake and oxidation, reduction in glucose utilization, accumulation of intramyocardial lipid droplets, and diastolic dysfunction.…”