Activation of PPARδ alters lipid metabolism in db/db mice

Abstract

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors, which heterodimerize with the retinoid X receptor and bind to peroxisome proliferator response elements in the promoters of regulated genes. Despite the wealth of information available on the function of PPARK K and PPARQ Q, relatively little is known about the most widely expressed PPAR subtype, PPARN N. Here we show that treatment of insulin resistant db/db mice with the PPARN N agonist L-165 041, at doses that had no effect on either glucose or triglycerides, raised total plasma cholesterol concentrations. The increased cholesterol was primarily associated with high density lipoprotein (HDL) particles, as shown by fast protein liquid chromatography analysis. These data were corroborated by the chemical analysis of the lipoproteins isolated by ultracentrifugation, demonstrating that treatment with L-165 041 produced an increase in circulating HDL without major changes in very low or low density lipoproteins. White adipose tissue lipoprotein lipase activity was reduced following treatment with the PPARN N ligand, but was increased by a PPARQ Q agonist. These data suggest both that PPARN N is involved in the regulation of cholesterol metabolism in db/db mice and that PPARN N ligands could potentially have therapeutic value. z 2000 Federation of European Biochemical Societies.

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].…”

PPARs Integrate the Mammalian Clock and Energy Metabolism

“…A class of PPAR γ ligands called thiazolidinediones (TZDs), such as rosiglitazone and pioglitazone, has been introduced in clinical practice for improving glycemic control via insulin sensitization in patients with type 2 diabetes [10]. Increasing evidence also points to a potential role of PPAR β / δ activators in improving insulin resistance and dyslipidemia [11]. In addition, some PPAR ligands are also potential therapeutic agents for treating hypertension, atherosclerosis, and diabetic nephropathy [1, 12, 13].…”

Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) ligands inhibit growth of UACC903 and MCF7 human cancer cell lines

“…This is due to their ability to increase serum HDL cholesterol (Leibowitz et al 2000;Oliver et al 2001;Sprecher et al 2006;van der Veen et al 2005;Wallace et al 2005), increase fatty acid catabolism in skeletal muscle, improve insulin resistance and inhibit inflammation (reviewed in (Barish et al 2006)). However, there is considerable controversy regarding the safety of PPARβ/δ ligands due to contradictory reports in the literature, in particular those describing effects in cancer models.…”