@article {Avery1, author = {Lindsay B. Avery and Namandj{\'e} N. Bumpus}, title = {Valproic Acid Is a Novel Activator of AMP-Activated Protein Kinase and Decreases Liver Mass, Hepatic Fat Accumulation, and Serum Glucose in Obese Mice}, volume = {85}, number = {1}, pages = {1--10}, year = {2014}, doi = {10.1124/mol.113.089755}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Valproic acid (VPA) is a widely prescribed anticonvulsant for the treatment of epilepsy. Here we demonstrate that VPA is a novel activator of AMP-activated protein kinase (AMPK), a key regulator of cellular metabolism, using primary mouse and human hepatocytes. Incubation of primary mouse hepatocytes with VPA resulted in increased levels of phosphorylated AMPK and acetyl-CoA carboxylase (ACC). This finding was recapitulated using primary human hepatocytes. Pretreatment of mouse hepatocytes with a small-molecule inhibitor of AMPK, Compound C (6-​[4-​(2-​piperidin-​1-​ylethoxy)​phenyl]​-​3-​pyridin-​4-​ylpyrazolo[1,5-​a]​pyrimidine), abrogated the phosphorylation of ACC following treatment with VPA. The cytochrome P450 inhibitor 1-aminobenzotriazole blocked the VPA-stimulated phosphorylation of AMPK, suggesting a requirement for biotransformation of VPA. In line with this, treatment of hepatocytes with metabolites of VPA resulted in increased phosphorylation of AMPK/ACC as compared with VPA. Treatment of ob/ob mice with VPA for 14 days resulted in decreased liver masses, hepatic fat accumulation, and serum glucose. These results paralleled those observed in mice treated with metformin. In addition, a targeted mass spectrometry{\textendash}based metabolomics assay revealed several small molecules that were differentially abundant in the serum of ob/ob mice treated with VPA as compared with vehicle-treated mice. These studies are the first to establish VPA and its metabolites as in vitro activators of AMPK.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/85/1/1}, eprint = {https://molpharm.aspetjournals.org/content/85/1/1.full.pdf}, journal = {Molecular Pharmacology} }