MD001, a Novel Peroxisome Proliferator-activated Receptor alpha/gamma Agonist, Improves Glucose and Lipid Metabolism

Abstract

Peroxisome proliferator-activated receptor (PPAR)-alpha/gamma dual agonists have been developed to treat metabolic diseases; however, most of them exhibit side effects such as body weight gain and oedema. Therefore, we developed a novel PPAR alpha/gamma dual agonist that modulates glucose and lipid metabolism without adverse effects. We synthesised novel compounds composed of coumarine and chalcone, determined their crystal structures, and then examined their binding affinity toward PPAR alpha/gamma. We investigated the expression of PPAR alpha and PPAR gamma target genes by chemicals in HepG2, differentiated 3T3-L1, and C2C12 cells. We examined the effect of chemicals on glucose and lipid metabolism in db/db mice. Only MD001 functions as a PPAR alpha/gamma dual agonist in vitro. MD001 increased the transcriptional activity of PPAR alpha and PPAR gamma, resulting in enhanced expression of genes related to beta-oxidation and fatty acid and glucose uptake. MD001 significantly improved blood metabolic parameters, including triglycerides, free fatty acids, and glucose, in db/db mice. In addition, MD001 ameliorated hepatic steatosis by stimulating beta-oxidation in vitro and in vivo. Our results demonstrated the beneficial effects of the novel compound MD001 on glucose and lipid metabolism as a PPAR alpha/gamma dual agonist. Consequently, MD001 may show potential as a novel drug candidate for the treatment of metabolic disorders.