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Resveratrol compounds are potent inhibitors of human holocarboxylase synthetase and cause a lean phenotype in Drosophila melanogaster brummer mutants (1045.39)

Acetyl‐CoA carboxylases (ACC) 1 and 2 are key enzymes in fatty acid (FA) synthesis and repression of FA degradation, respectively. Holocarboxylase synthetase (HLCS) catalyzes the covalent binding of the essential coenzyme biotin to ACCs. We hypothesized that dietary inhibitors of HLCS cause a loss of biotinylated ACCs, leading to a lean phenotype. The PEKISH library of natural compounds was screened for HLCS inhibitor activity in vitro; the screen suggested that resveratrol and its metabolites piceatannol and piceid inhibited HLCS by >90% at nutritionally relevant low micromolar levels (P<0.05 vs. vehicle, by ANOVA & posthoc, n=3). When NIH3T3 fibroblasts were treated with 25 µM piceatannol the levels of biotinylated ACC 1 and 2 decreased by 22% compared to controls. When Drosophila melanogaster brummer mutants, which are genetically predisposed to accumulate body fat, were fed diets supplemented with resveratrol compounds, body fat mass decreased by 50% (P<0.05, n=4) in male and female flies. We conclude that resveratrol compounds are potent inhibitors of HLCS‐dependent biotinylation of ACC 1 and 2, thereby contributing toward body fat loss in Drosophila melanogaster brummer mutants. Future studies will include mammalian models.