An inhibitory role of quercetin on adipocyte differentiation by mechanisms involving p27 protein stability and suppression of G1/S phase transition during preadipocyte proliferation

Abstract

With recent interest in bioactive food components as therapeutic tools in the prevention and treatment of obesity and related morbidities, the flavonol, quercetin has garnished considerable attention for its potent anti‐oxidant and anti‐inflammatory effects. Using 3T3‐L1 differentiation as a model of adipocyte hyperplasia, we observed that quercetin potently inhibited adipogenesis, but only when treated during the first 48 hrs of differentiation when preadipocytes (PA) transition through an obligatory phase of synchronous cell cycle progression. We also demonstrated that quercetin arrested PA proliferation during late G1 phase in a dose‐dependent manner with no measurable indices of toxicity. To determine a mechanistic role for quercetin in suppressing PA proliferation, we examined its effects on p27, a cyclin dependent kinase inhibitor known to regulate G1‐to‐S phase transition. We showed that quercetin inhibited the decrease in p27 protein abundance that is required for S phase progression, independent of changes in mRNA expression. We further demonstrated that quercetin increased p27 protein half‐life by mechanisms involving regulated proteolysis. Collectively, these data demonstrate that quercetin inhibits adipocyte differentiation by mechanisms involving p27 protein degradation and suppression of G1/S phase transition during PA proliferation. Supported by NIH‐NIDDK (R15DK082799)