Novel dual PPARα/γ agonists protect against liver steatosis and improve insulin sensitivity while avoiding side effects

Insulin resistance is a feature of type 2 diabetes mellitus (T2D), and is strongly interconnected with non-alcoholic fatty liver disease (NAFLD). Peroxisome-proliferator activated receptor gamma (PPARγ) and peroxisome-proliferator activated receptor alpha (PPARα) are master regulators of insulin sensitivity and lipid metabolism, respectively. Thiazolidinediones (TZDs) such as pioglitazone, which target PPARα/γ, are highly effective at treating insulin resistance and NAFLD, but their clinical utility has been restricted by side effects such as weight gain, adipocyte hypertrophy and fluid retention. Therefore, there is urgent need for new safer and effective drugs. Thus, we aimed to develop novel dual PPARα/γ agonists to avoid their known side effects while preserving their overall therapeutic effects. Here, we show that our novel agonists G4 and G5 strongly stimulate glucose transporter 4 (GLUT4) translocation to the cell membrane in skeletal muscle cells, and manifest weaker lipogenic effect in adipocytes. Moreover, G4 and G5 improve systemic glucose metabolism, hyperinsulinemia, hyperlipidemia, and markers of liver injury in high fructose diet-induced insulin resistant rats. Mechanistic studies revealed that G4 and G5 enhance GLUT4, and AMPK in skeletal muscle and protect against liver steatosis by upregulating PPARα and improve whole-body insulin sensitivity by increasing PPARγ. Despite this increase in PPARγ activity, G4 and G5 inhibit the unwanted side effects such as weight gain due to adiposity, hypertrophy of adipocytes, and fluid retention unlike TZDs. These findings identify G4 and G5 as promising dual PPARα/γ agonists for the treatment of NAFLD and insulin resistance with improved safety.