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.