Abstract
Peroxisome proliferator-activated receptor (PPAR) α/γ dual agonists have been developed to alleviate metabolic disorders and have the potential to be used as therapeutic agents for the treatment of type 2 diabetes. In this study, we investigated the effects of a newly synthesized PPAR α/γ dual agonist, 2-[4-(5-chlorobenzo [d] thiazol-2-yl) phenoxy]-2-methylpropanoic acid (MHY908) on type 2 diabetes in vitro and in vivo. To obtain initial evidence that MHY908 acts as a PPAR α/γ dual agonist, ChIP and reporter gene assays were conducted in AC2F rat liver cells, and to investigate the anti-diabetic effects and molecular mechanisms, eight-week-old, male db/db mice were allowed to eat ad libitum, placed on calorie restriction, or administered MHY908 (1 mg or 3 mg/kg/day) mixed in food for 4 weeks. Age-matched male db/m lean mice served as non-diabetic controls. It was found that MHY908 enhanced the binding and transcriptional activity of PPAR α and γ in AC2F cells, and it reduced serum glucose, triglyceride, and insulin levels, however increased adiponectin levels without body weight gain. In addition, MHY908 significantly improved hepatic steatosis by enhancing CPT-1 levels. Remarkably, MHY908 reduced endoplasmic reticulum (ER) stress and c-Jun N-terminal kinase (JNK) activation in the livers of db/db mice, and subsequently reduced insulin resistance. The study shows MHY908 has beneficial effects on type 2 diabetes by simultaneously activating PPAR α/γ and improving ER stress, and suggests that MHY908 could have a potent anti-diabetic effect as a PPAR α/γ dual agonist, and potential for the treatment of type 2 diabetes.
Highlights
The worldwide prevalence of obesity is steadily growing, and various systems that modulate the balance between energy intake and energy expenditure have been suggested to stave off obesity [1]
A chromatin immunoprecipitation (ChIP) assay was used to determine whether Peroxisome proliferator-activated receptor (PPAR) a and c activation by MHY908 (Fig. 2A) results in PPAR a and PPAR c binding to PPRE
We observed that interactions between PPAR a or PPAR c and PPRE were induced by MHY908 (Fig. 2B), indicating that MHY908 is a novel agonist of PPAR a and PPAR c
Summary
The worldwide prevalence of obesity is steadily growing, and various systems that modulate the balance between energy intake and energy expenditure have been suggested to stave off obesity [1]. Energy homeostasis is regulated by metabolic organs, such as, the liver, adipose tissues, and muscles, more so by liver as it is responsible for energy storage and supply. Alterations in liver function affect whole-body metabolism and energy homeostasis, and importantly underlie the development of metabolic diseases, such as, hyperglycemia, hyperlipidemia, fatty liver, insulin resistance, type 2 diabetes, and metabolic syndrome. Accumulating evidence suggests endoplasmic reticulum (ER) stress plays a substantial role in the pathogenesis of diabetes and contributes to insulin resistance [2,3], and it has been established that several PPAR a/c dual agonists enhance insulin sensitivity by inhibiting ER stress [4,5]. Recent studies suggest PPAR a activation stimulates lipid consumption by enhancing the expressions of genes that oxidize fatty acids, and that this ameliorates hyperlipidemia [7,8]. PPAR c controls lipid mobilization into adipocytes by promoting adipogenesis and regulating the expressions of adipocyte-secreted proteins and adipocytokines, such as, leptin and adiponectin, thereby reducing lipotoxicity [9]
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