1901-P: CK1 δ/ε Inhibitor PF-05006739 Ameliorates Hepatic Steatosis and Hyperinsulinemia in Dio Mice

The circadian rhythm allows for metabolic processes to be primed to anticipate the expected daily cycling of behaviors like food consumption and lipid storage. Previous genetic and epidemiological studies have implicated circadian disruption as a potential causal determinant for metabolic diseases such as obesity, diabetes and fatty liver. Here we leverage diet induced obese (DIO) mice to test the potential for circadian modulation by inhibition of casein kinase 1δ/ε (CK1 δ/ε) to improve endpoints in metabolic disease models. Our data reveal that the CK1 δ/ε inhibition with small molecule PF-05006739 was able to significantly lower fasted and fed insulin levels, fasted glucose and hepatic lipid content with a concomitant ∼9% decrease in body weight. PF-05006739 was also capable of shifting the gene expression of circadian oscillating transcripts in the liver, consistent with reported actions of this compound in previous preclinical evaluations. Furthermore, this shift in gene expression also correlated with a shift in respiratory exchange ratio (RER) and energy expenditure (EE) in vivo. Taken together these data suggest CK1 δ/ε inhibition as a potential therapeutic approach for metabolic diseases, specifically hyperinsulinemia and NAFLD/NASH. Disclosure M. Peloquin: Employee; Self; Pfizer Inc. J. Litchfield: Employee; Self; Pfizer Inc. B.B. Zhang: Employee; Spouse/Partner; Janssen Pharmaceuticals, Inc. Employee; Self; Pfizer Inc. Other Relationship; Self; Eli Lilly and Company. C. Chang: Employee; Self; Pfizer Inc. R.A. Miller: Employee; Self; Pfizer Inc. B. Bernardo: Employee; Self; Pfizer Inc. Employee; Spouse/Partner; Pfizer Inc. S. Luthra: None. C. Cortes: None. X. Li: Employee; Self; Pfizer Inc. C.J. Zou: None.