Lipidomics study of the regulatory effects of PPARδ agonist GW501516 in plasma of db/db diabetic mice

Type 2 diabetes mellitus (T2DM) is one of the most prevalent chronic metabolic disorder characterized by insulin resistance and relative insulin deficiency. PPARδ activation has been reported to have several beneficial effects in alleviating dyslipidemia and insulin resistance. GW501516, a synthetic PPARδ agonist, was developed to target hyperlipidemia and reported to alleviating insulin resistance in T2DM. Studies indicate that PPARδ activation by GW501516 can reduce adiposity, enhance β-oxidation of fatty acids, and improve insulin sensitivity in T2DM animal models. Despite its therapeutic promise, potential carcinogenic effects also have been reported. Therefore, a comprehensive non-targeted and targeted lipidomics study was carried out to evaluate the regulatory effect of GW501516 in the plasma of db/db mice. The results revealed that GW501516 is effective in reducing the accumulation of lipids in the fatty acid metabolism pathway and lipid classes including triglycerides and phosphatidylglycerols. Furthermore, activation of PPARδ by GW501516 demonstrated a beneficial effect on improving circulating cholesterol homeostasis. However, while the levels of hexosylceramides and sphingomyelin were partially reversed, ceramide levels, which are negatively associated with insulin sensitivity, were significantly elevated by GW501516. Despite these mixed outcomes, the study highlights both the promising therapeutic potential of PPARδ activation in metabolic disorders and the safety concerns regarding long-term clinical use. The findings provide valuable insights into the impact of GW501516-induced PPARδ activation on lipid metabolism in T2DM, contributing to a better understanding of its therapeutic potential and risks.