Abstract
Recently, agonists targeting multiple peroxisome proliferator-activated receptors (PPARs) have been developed to improve metabolic disorders and minimize the side effects of selective PPAR agonists such as weight gain and dyslipidemia. We newly synthesized six 2-methyl-2-(o-tolyloxy)propanoic acid derivatives based on the structure of a well-known PPAR pan agonist, bezafibrate. Of six compounds, MHY2013 was screened as the strongest activator of three PPAR subtypes based on protein docking simulation and luciferase assays. When treated orally in db/db mice, MHY2013 ameliorated obesity-induced insulin resistance, dyslipidemia, and hepatic steatosis without changes of the body weight and levels of liver and kidney injury markers. MHY2013 decreased the serum triglyceride and fatty acid levels, which is associated with an increase in fatty acid oxidation signaling in the liver and thermogenic signaling on white adipose tissue, respectively. Furthermore, MHY2013 markedly increased serum levels of insulin-sensitizing hormones including fibroblast growth factor 21 (FGF21) and adiponectin. In conclusion, this study suggests that, MHY2013 is a novel PPAR pan agonist that improves obesity-induced insulin resistance, dyslipidemia and hepatic steatosis and elevates insulin-sensitizing hormones in the blood.
Highlights
Each peroxisome proliferator-activated receptors (PPARs) subtype plays a pivotal role in regulating tissue metabolism in hormone-dependent and independent manners [1]
To search for powerful PPAR pan agonists, we newly synthesized six 2-methyl-2-(o-tolyloxy)propanoic acid derivatives based on the structure of the well-known PPAR pan agonist bezafibrate (Supplementary Method 1 and Supplementary Table 1 )
The binding affinities of WY14643, GW501516, and rosiglitazone to PPARα, PPARβ/δ, and PPARγ, respectively, were −7.93, −9.68, and −8.03 kcal/mol, respectively, whereas the binding affinities of MHY2013 to PPARα, PPARβ/δ, and PPARγ were −7.94, −9.2, and −8.69 kcal/mol, respectively (Figure 2A, B, C). These results suggest that the binding affinity of MHY2013 to each PPAR subtype may be comparable to that of the positive controls
Summary
Each PPAR subtype plays a pivotal role in regulating tissue metabolism in hormone-dependent and independent manners [1]. PPAR subtype agonists are in clinical use for metabolic diseases, including type 2 diabetes, cardiovascular diseases, etc. In the case of PPARγ selectively agonistic glitazone-type drugs, side effects such as dyslipidemia, heart failure, and weight gain have been reported in clinical stages [7]. Clinical and animal studies have demonstrated beneficial effects of PPAR dual and pan agonists, with fewer side effects compared to selective PPAR agonistic drugs, possibly by providing complementary effects [8]. MHY2013 elevated blood FGF21 and adiponectin and increased adipose tissue browning, thereby contributing to improved obesity-induced insulin resistance, hepatic steatosis, and dyslipidemia without affecting body weight. Our study provides a molecular rationale for further development of MHY2013 as treatment of metabolic disorders
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