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

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.

Flavonoids: nutraceutical potential for counteracting muscle atrophy

“…Three different energy systems, including aerobic oxidative, anaerobic glycolytic, and phosphagen systems, are responsible for transforming chemical energy into physical force in skeletal muscle, thereby allowing humans to perform various physical activities (Frontera and Ochala, 2015;Wells et al, 2009). Secondly, along with other two organs, hepatic and adipose tissues, skeletal muscle is a representative organ to metabolize glucose, free fatty acid, and protein (Kim et al, 2019c). Therefore, skeletal muscle is a wellknown target organ not only for treating metabolic diseases and symptoms, such as obesity, type 2 diabetes, hyperglycemia, and hyperlipidemia but also for maintaining body temperature (Frontera and Ochala, 2015;Kim et al, 2019c).…”

Curcumin promotes progression of AApoAII amyloidosis and peroxisome proliferation in mice by activating the PPARα signaling pathway

“…PPARα agonists (e.g., fibrates) or PPARr agonists (e.g., thiazolidinedione) play important roles in the treatment of hyperlipidemia and type 2 diabetes in the clinic. PPARα/r dual agonists are also under development to treat more complex metabolic diseases, but some exhibit side effects and cause liver or cardiac dysfunction [64, 65]. In clinical trials, it has been demonstrated that supplementation with curcumin at a high dose is safe in humans [66, 67].…”

The nutrigenomic metabolite L‑carnitine directly modulates the activity and expression of nuclear receptors in adipocytes, liver and muscle cells

“…Therefore, primary human skeletal muscle cells were investigated together with the WRL68 cell line, representative of mature human hepatocytes, as well as differentiated 3T3L1 cells, representative of mature murine adipocytes. The combination of human hepatocyte cell lines and murine adipocyte cell lines has already been successfully used in previous studies [18,19].…”