Activation of peroxisome proliferator-activated receptor δ induces fatty acid β-oxidation in skeletal muscle and attenuates metabolic syndrome

Abstract

In this study, we defined the role of peroxisome proliferator-activated receptor ␤͞␦ (PPAR␦) in metabolic homeostasis by using subtype selective agonists. Analysis of rat L6 myotubes treated with the PPAR␦ subtype-selective agonist, GW501516, by the Affymetrix oligonucleotide microarrays revealed that PPAR␦ controls fatty acid oxidation by regulating genes involved in fatty acid transport, ␤-oxidation, and mitochondrial respiration. Similar PPAR␦-mediated gene activation was observed in the skeletal muscle of GW501516-treated mice. Accordingly, GW501516 treatment induced fatty acid ␤-oxidation in L6 myotubes as well as in mouse skeletal muscles. Administration of GW501516 to mice fed a high-fat diet ameliorated diet-induced obesity and insulin resistance, an effect accompanied by enhanced metabolic rate and fatty acid ␤-oxidation, proliferation of mitochondria, and a marked reduction of lipid droplets in skeletal muscles. Despite a modest body weight change relative to vehicle-treated mice, GW501516 treatment also markedly improved diabetes as revealed by the decrease in plasma glucose and blood insulin levels in genetically obese ob͞ob mice. These data suggest that PPAR␦ is pivotal to control the program for fatty acid oxidation in the skeletal muscle, thereby ameliorating obesity and insulin resistance through its activation in obese animals.obesity ͉ insulin resistance ͉ thermogenesis ͉ pancreatic ␤-cell ͉ PGC-1␣

Heritability and genetic etiology of habitual physical activity: a twin study with objective measures

“…PPARd, the predominant PPAR isoform in skeletal muscle, is co-activated by PGC-1a (Wang et al 2003). Much like PGC-1a, PPARd regulates fatty acid oxidation via the transcription of genes involved in b-oxidation and energy uncoupling (Tanaka et al 2003;Wang et al 2003). In addition, PPARd is involved in regulating bone turnover (Scholtysek et al 2013).…”

Features of the metabolic syndrome are modulated by an interaction between the peroxisome proliferator-activated receptor-delta −87T>C polymorphism and dietary fat in French-Canadians

“…6, 7 The fatty acid utilization in the skeletal muscle could be enhanced in À87C carriers through a greater activation by PPAR-delta of genes involved in long chain fatty acids b-oxidation. 8,10 Therefore, carriers of the À87C allele might be protected from deleterious effects of a highfat diet on the lipid metabolism in comparison to the general population. It has also been demonstrated by Oliver et al 7 that PPAR-delta increases cholesterol efflux from macrophage, fibroblast and intestinal cells, in part through an increase in the expression of the ABCA1 reverse cholesterol transporter.…”

“…5 It has been shown that PPAR-delta is involved in the regulation of genes participating in lipid and lipoprotein metabolism 6,7 as well as in adipose tissue and muscle fatty acid oxidation. [8][9][10] Its role in cellular response to inflammation is also well characterized. 11,12 As for PPARa and PPARg, fatty acids are natural ligands of PPARdelta.…”

Variation in the peroxisome proliferator-activated receptor δ gene in relation to common metabolic traits in 7,495 middle-aged white people

“…Increased Ppard expression in adipose tissue in mice is associated with reduced adiposity and lower serum lipid levels [9,10]. In addition, activation of PPARδ by treatment with a synthetic agonist ameliorates diet-induced obesity and insulin resistance in mice [10] and improves circulating lipid profiles in both obese rhesus monkeys and db/db mice [11,12]. In line with the outcome of studies in rodents, expression profiling studies in humans have shown an increase in PPARD expression following endurance exercise [13,14].…”

“…Additionally, a recent study of genetically modified mice provides evidence that PPARδ regulates glucose metabolism and insulin sensitivity in both skeletal muscle and the liver, interestingly indicating a subtle PPARδ-controlled change in substrate utilisation [8]. Increased Ppard expression in adipose tissue in mice is associated with reduced adiposity and lower serum lipid levels [9,10]. In addition, activation of PPARδ by treatment with a synthetic agonist ameliorates diet-induced obesity and insulin resistance in mice [10] and improves circulating lipid profiles in both obese rhesus monkeys and db/db mice [11,12].…”