The Peroxisome Proliferator-Activated Receptor α (PPARα) Agonist Pemafibrate Protects against Diet-Induced Obesity in Mice

Int J Mol Sci. 2018 Jul 23;19(7):2148. doi: 10.3390/ijms19072148.


Peroxisome proliferator-activated receptor α (PPARα) is a therapeutic target for hyperlipidemia. Pemafibrate (K-877) is a new selective PPARα modulator activating PPARα transcriptional activity. To determine the effects of pemafibrate on diet-induced obesity, wild-type mice were fed a high-fat diet (HFD) containing pemafibrate for 12 weeks. Like fenofibrate, pemafibrate significantly suppressed HFD-induced body weight gain; decreased plasma glucose, insulin and triglyceride (TG) levels; and increased plasma fibroblast growth factor 21 (FGF21). However, compared to the dose of fenofibrate, a relatively low dose of pemafibrate showed these effects. Pemafibrate activated PPARα transcriptional activity in the liver, increasing both hepatic expression and plasma levels of FGF21. Additionally, pemafibrate increased the expression of genes involved in thermogenesis and fatty acid oxidation, including Ucp1, Cidea and Cpt1b in inguinal adipose tissue (iWAT) and the mitochondrial marker Elovl3 in brown adipose tissue (BAT). Therefore, pemafibrate activates thermogenesis in iWAT and BAT by increasing plasma levels of FGF21. Additionally, pemafibrate induced the expression of Atgl and Hsl in epididymal white adipose tissue, leading to the activation of lipolysis. Taken together, pemafibrate suppresses diet-induced obesity in mice and improves their obesity-related metabolic abnormalities. We propose that pemafibrate may be useful for the suppression and improvement of obesity-induced metabolic abnormalities.

Keywords: FGF21; PPARα; SPPARMα; lipid metabolism; obesity; pemafibrate.

MeSH terms

  • Acetyltransferases / genetics
  • Acetyltransferases / metabolism
  • Adipose Tissue / drug effects
  • Adipose Tissue / metabolism
  • Animals
  • Anti-Obesity Agents / administration & dosage
  • Anti-Obesity Agents / pharmacology
  • Anti-Obesity Agents / therapeutic use*
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Benzoxazoles / administration & dosage
  • Benzoxazoles / pharmacology
  • Benzoxazoles / therapeutic use*
  • Blood Glucose / metabolism
  • Butyrates / administration & dosage
  • Butyrates / pharmacology
  • Butyrates / therapeutic use*
  • Carnitine O-Palmitoyltransferase / genetics
  • Carnitine O-Palmitoyltransferase / metabolism
  • Diet, High-Fat / adverse effects
  • Fatty Acid Elongases
  • Insulin / blood
  • Lipolysis
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Obesity / drug therapy*
  • Obesity / etiology
  • Obesity / prevention & control
  • PPAR alpha / antagonists & inhibitors*
  • Triglycerides / blood
  • Uncoupling Protein 1 / genetics
  • Uncoupling Protein 1 / metabolism


  • (R)-2-(3-((benzoxazol-2-yl-d4 (3-(4-methoxyphenoxy-d7)propyl)amino)methyl)phenoxy) butanoic acid
  • Anti-Obesity Agents
  • Apoptosis Regulatory Proteins
  • Benzoxazoles
  • Blood Glucose
  • Butyrates
  • Cidea protein, mouse
  • Elovl3 protein, mouse
  • Insulin
  • PPAR alpha
  • Triglycerides
  • Ucp1 protein, mouse
  • Uncoupling Protein 1
  • Acetyltransferases
  • Fatty Acid Elongases
  • CPT1B protein, mouse
  • Carnitine O-Palmitoyltransferase