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Aims/Hypothesis Current drugs used to treat metabolic diseases such as obesity and type 2 diabetes have limited efficacy in directly normalising muscle insulin action, while exercise is effective in enhancing this aspect of metabolic disease. We recently identified Scriptaid as a compound that can replicate aspects of the exercise adaptive response, through disruption of the class IIa HDAC corepressor complex. The Aim of this study was to determine the effect of Scriptaid on muscle insulin action in obesity. Materials and Methods Diet-induced obese mice were administered Scriptaid (1 mg/kg) via daily i.p. injection for four weeks. Whole body and skeletal muscle metabolic phenotyping of mice was performed in addition to echocardiography to assess cardiac morphology and function. Results Scriptaid treatment had no effect on body weight or composition, but did increase energy expenditure, supported by increased lipid oxidation, while food intake was also increased. Scriptaid enhanced the expression of oxidative genes and proteins, increased fatty acid oxidation and reduced triglycerides and diacylglycerides in skeletal muscle. Furthermore, ex vivo insulin-stimulated glucose uptake by skeletal muscle was enhanced. Surprisingly, heart weight was reduced in Scriptaid-treated mice and was associated with enhanced expression of genes involved in oxidative metabolism in the heart. Scriptaid also improved indices of both diastolic and systolic cardiac function. Conclusion These data show that pharmacological targeting of the class IIa HDACs corepressor complex with Scriptaid could be used to enhance muscle insulin action and cardiac function in obesity.