Effect of the Flavonoid Quercetin on Adipocytes

Obesity is an urgent global public health concern as prevalence rates continue to increase, especially among children. At the cellular level obesity is defined by an increase in adipocyte number (hyperplasia) and size (hypertrophy). Both lead to the dysfunction of adipose tissue, which has been identified as the link between obesity and chronic disease. Bioactive compounds, naturally occurring in fruits and vegetables, hold enormous potential in regulating adipocyte biology. Quercetin, the most commonly consumed dietary flavonoid, is a strong potential anti-obesity agent that has been implicated as an AMP-activated protein kinase (AMPK) activator and shown to ameliorate symptoms of metabolic syndrome in vivo. Here we investigated quercetin’s effect on (1) adipogenesis, the process of increasing adipocyte number, and (2) metabolism of mature adipocytes. In 3T3-L1 preadipocytes, quercetin dose-dependently inhibited adipogenesis, as evidenced by decreased lipid accumulation and expression of adipogenic markers such as peroxisome proliferator-activated receptor (PPAR) γ, CCAAT/ enhancer binding protein (C/EBP) α, adipocyte fatty acid binding protein 2 (aP2), and acetyl-CoA carboxylase (ACC) on mRNA and protein levels. This inhibitory effect was limited to the early stages of adipogenesis (0-36 hours), and quercetin treatment altered the normal expression pattern of cell cycle related genes Cyclin A and p27, indicating quercetin may inhibit adipogenesis through cell cycle events. We next investigated quercetin’s ability to activate AMPK and the metabolic pathways related to AMPK activation: lipolysis and b-oxidation. Quercetin increased phosphorylation of AMPK and its downstream target ACC. Further, quercetin treatment (100μM) increased free fatty acid content in the media through an AMPK-dependent mechanism. Quercetin up-regulated mRNA expression of uncoupling proteins 3 (UCP3) and peroxisome proliferator-activated receptor-gamma co-activator 1 alpha (PGC-1a), indicating that quercetin may induce mitochondrial oxidative pathways, also through an AMPK-dependent pathway. These findings suggest (1) quercetin inhibits adipogenesis through the regulation of early cell cycle events required for adipogenic differentiation, and (2) quercetin’s activation of AMPK induces lipolytic and oxidative pathways. Taken together, quercetin could be further developed as an anti-obesity agent because of its potential to inhibit both hyperplasia and hypertrophy in vitro