Curc-mPEG45 lowered BW gain and serum TGs levels. Curc-mPEG454 reduced hepatic steatosis by decreasing TGs content, decreasing lipid accumulation, and attenuating macrovesicular and microvesicular steatosis. Curc-mPEG454 reduced hepatic PPARγ and CD36 protein and mRNA expression. Curc-mPEG454 activated hepatic p-CREB. Here, CREB1 is linked to fatty liver disease.