Research ArticleMetabolism

Identification of entacapone as a chemical inhibitor of FTO mediating metabolic regulation through FOXO1

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Science Translational Medicine  17 Apr 2019:
Vol. 11, Issue 488, eaau7116
DOI: 10.1126/scitranslmed.aau7116

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The skinny on FTO

Although the fat mass and obesity-associated gene FTO has been linked to genetic risk of obesity, the mRNA demethylase that it encodes has proven difficult to therapeutically target. From a screen of approved drugs, Peng et al. identified entacapone, a catechol-O-methyltransferase inhibitor used in the treatment of Parkinson’s disease, as an inhibitor of FTO. In vivo administration of entacapone improved body weight and glucose tolerance and increased adipose thermogenesis in mice, which the authors tied to decreased FTO-catalyzed m6A demethylation of FOXO1 mRNA. Further studies will need to confirm the repurposing potential of entacapone for obesity or metabolic disease in humans.

Abstract

Recent studies have established the involvement of the fat mass and obesity-associated gene (FTO) in metabolic disorders such as obesity and diabetes. However, the precise molecular mechanism by which FTO regulates metabolism remains unknown. Here, we used a structure-based virtual screening of U.S. Food and Drug Administration–approved drugs to identify entacapone as a potential FTO inhibitor. Using structural and biochemical studies, we showed that entacapone directly bound to FTO and inhibited FTO activity in vitro. Furthermore, entacapone administration reduced body weight and lowered fasting blood glucose concentrations in diet-induced obese mice. We identified the transcription factor forkhead box protein O1 (FOXO1) mRNA as a direct substrate of FTO, and demonstrated that entacapone elicited its effects on gluconeogenesis in the liver and thermogenesis in adipose tissues in mice by acting on an FTO-FOXO1 regulatory axis.

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