Abstract
Peroxisome proliferator-activated receptor (PPAR)-α/γ 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 PPARα/γ 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 PPARα/γ. We investigated the expression of PPARα and PPARγ 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 PPARα/γ dual agonist in vitro. MD001 increased the transcriptional activity of PPARα and PPARγ, resulting in enhanced expression of genes related to β-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 β-oxidation in vitro and in vivo. Our results demonstrated the beneficial effects of the novel compound MD001 on glucose and lipid metabolism as a PPARα/γ dual agonist. Consequently, MD001 may show potential as a novel drug candidate for the treatment of metabolic disorders.
Highlights
Energy metabolism is maintained by three major organs - adipose tissue, liver, and muscle - and crosstalk among them is essential for homeostasis
The synthesis commenced with a well-known Pechmann condensation of commercially available (1)[24] and ethyl benzoyl acetate to afford a roughly 1:1 mixture of 2a and 2b owing to the presence of two isomeric ortho and para hydroxyl groups to the methyl group
Despite our efforts to force the reaction with various Lewis acids such as BF3∙OEt2, SnCl4, and TiCl4, all failed to yield any of the desired products
Summary
Energy metabolism is maintained by three major organs - adipose tissue, liver, and muscle - and crosstalk among them is essential for homeostasis. PPARγ activation by TZD increases the expression of CD36 and FABP for lipid storage and the expression of glucose transporter for glucose uptake in adipocytes, liver, and skeletal muscle, thereby reducing the amount of fatty acid and glucose levels in blood by increasing insulin sensitivity. Since TZD induces storage of fatty acids and glucose rather than consumption in the cell, it has been associated with several concerns, including body weight gain and myocardial infarction[12,13,14]. A majority of these drugs showed severe adverse effects, including heart failure, renal failure, urinary cancer, body weight gain, stroke, and anemia[18,19,20,21,22], necessitating the development of novel PPARα/γ dual agonists without side-effects. We tried to synthesise various constitutional isomers of Int B to find a novel agonist targeting PPARs and investigate its ability to improve metabolic disorders in vitro and in vivo
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