Activation of Peroxisome Proliferator–Activated Receptor (PPAR)δ Promotes Reversal of Multiple Metabolic Abnormalities, Reduces Oxidative Stress, and Increases Fatty Acid Oxidation in Moderately Obese Men

Abstract

OBJECTIVE-Pharmacological use of peroxisome proliferatoractivated receptor (PPAR)␦ agonists and transgenic overexpression of PPAR␦ in mice suggest amelioration of features of the metabolic syndrome through enhanced fat oxidation in skeletal muscle. We hypothesize a similar mechanism operates in humans. RESEARCH DESIGN AND METHODS-The, and placebo were given in a double-blind, randomized, three-parallel group, 2-week study to six healthy moderately overweight subjects in each group. Metabolic evaluation was made before and after treatment including liver fat quantification, fasting blood samples, a 6-h meal tolerance test with stable isotope fatty acids, skeletal muscle biopsy for gene expression, and urinary isoprostanes for global oxidative stress. RESULTS-Treatment with GW501516showed statistically significant reductions in fasting plasma triglycerides (Ϫ30%), apolipoprotein B (Ϫ26%), LDL cholesterol (Ϫ23%), and insulin (Ϫ11%), whereas HDL cholesterol was unchanged. A 20% reduction in liver fat content (P Ͻ 0.05) and 30% reduction in urinary isoprostanes (P ϭ 0.01) were also observed. Except for a lowering of triglycerides (Ϫ30%, P Ͻ 0.05), none of these changes were observed in response to GW590735. The relative proportion of exhaled CO 2 directly originating from the fat content of the meal was increased (P Ͻ 0.05) in response to GW501516, and skeletal muscle expression of carnitine palmitoyl-transferase 1b (CPT1b) was also significantly increased.CONCLUSIONS-The PPAR␦ agonist GW501516 reverses multiple abnormalities associated with the metabolic syndrome without increasing oxidative stress. The effect is probably caused by increased fat oxidation in skeletal muscle. Diabetes 57: 332-339, 2008

The new‐generation pan‐peroxisome proliferator‐activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis

“…During a 48‐week clinical trial in patients with biopsy‐proven NASH, fenofibrate significantly decreased ballooning and improved metabolic parameters but not inflammation or steatosis 16. Selective PPARδ agonists have not been investigated in patients with NASH, but in overweight subjects GW501516 and MBX‐8025 improved metabolic parameters during a 2‐week and 8‐week duration trial, respectively 17, 18. More recently, the dual PPARα/δ agonist elafibranor (GFT505) achieved improvement in steatohepatitis without fibrosis worsening in patients with a NAS score ≥4 and decreased fibrosis in the subgroup of patients with NASH who responded to GFT505 47.…”

“…In patients, the PPARα agonist fenofibrate had limited efficacy on NASH but a significant effect on hepatocyte ballooning 16. Some but not all PPARδ agonists have had beneficial effects in preclinical models of NASH 17, 18. Elafibranor (GFT505), which combines PPARα and PPARδ activation, improved metabolic disorders and reduced the severity of steatohepatitis and fibrosis in several animal models and in patients with NASH 19.…”

PPARs and adipocyte function

“…In this respect use of the PPAR agonist GW501516 has shown clinical promise in a small scale trial involving healthy male volunteers [86]. In parallel the current (and future) development of selective modulators of PPAR activity promises to provide novel therapies to treat insulin resistance without the concomitant side effects of weight gain, fluid retention, and potentially increased cardiovascular risk associated with the use of TZDs.…”

“…Most tantalisingly, PPAR ligands ameliorated diet-induced obesity (and insulin resistance) in high-fat dietfed mice [84]. While short-term (4-month) treatment of obese rhesus monkeys with GW501516 did not affect body weight [85], acute (2-week) administration of the same compound to six healthy, male human subjects was associated with a weight-loss trend [86].…”

Adipose tissue fatty acid metabolism in insulin-resistant men

“…An impairment of NEFA uptake by muscle has been demonstrated in obesity [13], in impaired glucose tolerance [14] and in type 2 diabetes [15]. Increasing NEFA oxidation in insulin-resistant men by peroxisome proliferator-activated receptor-δ activation markedly lowers NEFA concentrations [16].…”