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. 2018 Jul 23;19(7):2148.
doi: 10.3390/ijms19072148.

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

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Free PMC article

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

Masaya Araki et al. Int J Mol Sci. .
Free PMC article

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.

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

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Pemafibrate reduces plasma lipid levels in WT mice fed with high-fat diet (HFD) for 12 weeks. Six-week-old male WT mice were fed HFD plus pemafibrate (0.00033%) or fenofibrate (0.2%) for 12 weeks (A); (B) Representative pictures of mice; (C) body growth curve; †† p < 0.01; untreated mice vs. pemafibrate- and fenofibrate-treated mice; (D) liver weight; (E) eWAT weight; (F) iWAT weight; (G) BAT weight; and concentrations of (H) plasma glucose; (I) insulin; (J) TG; (K) TC; (L) FFA; (M) FGF21; (N) AST and (O) ALT. All values are the means ± standard error of the mean (SEM). n = 9 per group; * p < 0.05; ** p < 0.01.
Figure 2
Figure 2
Histological analysis shows that pemafibrate reduces lipid content and cell size in liver and WATs in high-fat diet (HFD)-fed WT mice. Six-week-old male WT mice were fed HFD plus pemafibrate (0.00033%) or fenofibrate (0.2%) for 12 weeks. HE staining analysis in liver (A), eWAT (D), iWAT (E) and BAT (F). Liver TG (B) and TC (C) concentrations; All values are the means ± SEM. n = 9 per group; Scale bar: 100 μm.
Figure 3
Figure 3
Oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) in high-fat diet (HFD)-fed WT mice treated with pemafibrate. Six-week-old male WT mice were fed HFD plus pemafibrate (0.00033%) or fenofibrate (0.2%) for 10 weeks. (A,B) Results of OGTT of these mice. Plasma glucose (A) and insulin levels (B) during OGTT. (C) Results of ITT of mice treated with pemafibrate for 11 weeks. Plasma glucose levels during ITT; All values are the means ± SEM. n = 9 per group; †† p < 0.01; untreated mice vs. pemafibrate- and fenofibrate-treated mice.
Figure 4
Figure 4
Gene expression in WT mice fed with high-fat diet (HFD) plus pemafibrate for 12 weeks. Six-week-old male WT mice were fed HFD and treated with or without pemafibrate (0.00033%) or fenofibrate (0.2%) for 12 weeks. Gene expression profiles of the liver (A), eWAT (B), iWAT (C) and BAT (D); All values are the means ± SEM. n = 9 per group; * p < 0.05; ** p < 0.01.
Figure 5
Figure 5
Pemafibrate reduces plasma lipid levels in high-fat diet (HFD)-fed WT mice treated with pemafibrate. Six-week-old male WT mice were fed HFD for 8 weeks and treated with pemafibrate (0.00033%) or fenofibrate (0.2%) for 4 weeks (A). (B) Representative pictures of mice; (C) body growth curve, ↓; start of agonist treatment, ‡‡ p < 0.01; untreated mice vs. fenofibrate-treated mice, †† p < 0.01; untreated mice vs. pemafibrate- and fenofibrate-treated mice; (D) liver weight; (E) eWAT weight; (F) iWAT weight; (G) BAT weight; and concentrations of (H) plasma glucose, (I) insulin, (J) TG, (K) TC, (L) FFA, (M) FGF21, (N) AST and (O) ALT. All values are the means ± SEM. n = 9 per group; * p < 0.05; ** p < 0.01.
Figure 6
Figure 6
Oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) of high-fat diet (HFD)-induced obese mice treated with pemafibrate. Six-week-old male WT mice were fed HFD for 8 weeks and then treated with pemafibrate (0.00033%) or fenofibrate (0.2%). (A,B) Results of OGTT of mice treated with pemafibrate or fenofibrate for 2 weeks. Plasma glucose (A) and insulin levels (B) during OGTT. (C) Results of ITT of mice treated with pemafibrate or fenofibrate for 3 weeks. Plasma glucose levels during ITT. All values are the means ± SEM. n = 9 per group; †† p < 0.01 untreated mice vs. pemafibrate- and fenofibrate-treated mice.
Figure 7
Figure 7
Pemafibrate reduces plasma lipid levels in WT mice fed with (modest-fat) MF diet. Eleven-week-old male WT mice were fed MF diet plus pemafibrate (0.001%) or fenofibrate (0.2%) for 1 week. Body weight (A); liver weight (B); eWAT weight (C); iWAT weight (D); BAT weight (E); muscle weight (F); and concentrations of plasma glucose (G), insulin (H), TG (I), TC (J), FFA (K), FGF21 (L), AST (M) and ALT (N). All values are the means ± SEM. n = 8 per group; * p < 0.05; ** p < 0.01.
Figure 8
Figure 8
Histological analysis shows that pemafibrate reduces lipid contents and cell size in the liver and WATs in MF-diet fed WT mice. Eleven-week-old male WT mice were fed MF diet plus pemafibrate (0.001%) or fenofibrate (0.1%) for 1 week. HE staining analysis of liver (A), eWAT (D), iWAT (E), BAT (F) and concentrations of liver TG (B) and TC (C). All values are the means ± SEM. n = 8 per group; ** p < 0.01; n = 9–13 per group. Scale bar: 100 μm.
Figure 9
Figure 9
Gene expression in WT mice fed with MF diet plus pemafibrate for 1 week. Eleven-week-old male WT and FGF21 KO mice were fed MF diet plus pemafibrate (0.001%) or fenofibrate (0.1%) for 1 week. Gene expression profiles of the liver (A), eWAT (B), iWAT (C) and BAT (D). All values are the means ± SEM. n = 8 per group; * p < 0.05; ** p < 0.01.

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