Abstract
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.
Highlights
Dysregulation of nutrient homeostasis is a common character of metabolic disorders, such as obesity, diabetes, cardiovascular diseases and fatty liver disease
To compare the effects of Peroxisome proliferator-activated receptor α (PPARα) agonists on the progression of obesity, 6-week-old male wild type (WT) mice were fed high-fat diet (HFD) containing 0.00033% pemafibrate or 0.2% fenofibrate for 12 weeks (Figure 1A)
Our results show that pemafibrate significantly suppressed HFD-induced body weight gain, decreased plasma glucose, insulin and triglyceride (TG) levels and increased plasma fibroblast growth factor 21 (FGF21) expression in diet-induced obesity (DIO) mice
Summary
Dysregulation of nutrient homeostasis is a common character of metabolic disorders, such as obesity, diabetes, cardiovascular diseases and fatty liver disease. Nutrient homeostasis is tightly maintained via the balance between energy production and energy utilization. The rapid increase in the prevalence of obesity-related metabolic diseases, such as diabetes, hyperlipidemia, hypertension and cancer, is a serious health problem worldwide [1]. Obesity occurs when an individual’s caloric intake exceeds their energy expenditure. Fat accumulates in white adipose tissues (WATs) and in a variety of other tissues. Obesity results in insulin resistance, which leads to obesity-related metabolic disorders
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