Novel FoxO1 inhibitor, JY-2, ameliorates palmitic acid-induced lipotoxicity and gluconeogenesis in a murine model

Forkhead transcription factor forkhead box O1 (FoxO1) plays an important role in glucose and lipid metabolism, contributing to the pathogenesis of metabolic disorders. This study aimed to discover a novel FoxO1 inhibitor as a potential new anti-diabetic drug candidate, and describes the biological effects of JY-2, 5-(2,4-dichlorophenyl)-3-(pyridin-2-yl)-1,2,4-oxadiazole in vitro and in vivo. JY-2 inhibited FoxO1 transcriptional activity in a concentration-dependent manner, with an IC₅₀ value of 22 μM. The inhibitory effects of JY-2 on FoxO3a and FoxO4 appeared to be weaker than that on FoxO1. Consistent with its inhibitory effect on FoxO1, JY-2 reduced the palmitic acid (PA)-stimulated mRNA expression of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK), two key enzymes involved in gluconeogenesis in HepG2 cells. In association with the reduced expression of lipid metabolism genes, triglyceride accumulation was also reduced by JY-2, as determined by Oil Red O staining. In addition, JY-2 restored PA-impaired glucose-stimulated insulin secretion (GSIS), in conjunction with an increased mRNA expression of PDX1, MafA, and insulin in INS-1 cells. The in vivo efficacy of JY-2 was examined using C57BL/6J, db/db, and high fat-diet induced obese and diabetic (DIO) mice models, and showed that JY-2 improved glucose tolerance, in parallel with a reduced mRNA expression of gluconeogenic genes. Pharmacokinetic analysis revealed that JY-2 exhibited excellent oral bioavailability (98%), with little adverse effects. These results demonstrated that the novel FoxO1 inhibitor, JY-2, may exert beneficial anti-diabetic effects and that it warrants further investigation as a novel anti-diabetic drug candidate.