Characterizing Novel PPAR Agonists Derived from Cashew Nut Shell Liquid for the Treatment of Metabolic Disease

The peroxisome proliferator-activated receptors (PPARα,γ,β) are important druggable targets to treat patients with type 2 diabetes and dyslipidemia. However, current PPAR agonists lead to serious adverse effects, including edema, cardiovascular disease, weight gain, and bone fractures. We hypothesized that PPAR agonists with properties similar to their endogenous ligands may be therapeutically desirable for treatment of metabolic disease while limiting the adverse effects. Using in vitro models, we found that a number of LDT compounds derived from cashew nut shell liquid acted on the PPAR receptors. Specifically, we identified LDT409 that showed partial agonistic activity and equal binding affinities to PPARα and PPARγ receptors with reduced affinity for PPARβ. Using diet-induced obese mice, we determined that LDT409 was protective from high fat diet-induced weight gain, fatty liver disease, and insulin resistance without increasing markers of edema, bone loss, and heart failure. Together, these studies suggest that LDT compounds will be efficacious to treat metabolic disease and may have fewer adverse effects compared to traditional PPAR agonists.M.Sc.2019-04-15 00:00:0