Quercetin enhances muscle FNDC5/irisin, partly through AMPK activation, and induces white adipose tissue browning in high-fat-fed rats.

Irisin is a myokine released during physical activity that contributes to the browning of white adipose tissue (WAT), providing various metabolic benefits. We previously demonstrated that supplementation with the flavonoid quercetin (Q) alleviates high-fat diet (HFD) induced visceral WAT hypertrophy, inflammation, and insulin resistance in rats. In this study, we aimed to investigate whether these beneficial effects might be associated with the ability of Q to upregulate muscle fibronectin type 3 domain-containing protein 5 (FNDC5)/irisin and uncoupling protein-1 (UCP-1), along with other brown fat markers in inguinal WAT (iWAT). HFD-fed rats for 6 weeks showed reduced muscle protein levels of FNDC5 and peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) compared to the control (Ctrl) group. Q supplementation (20 mg/kg/body weight (BW)/day) reverted these adverse effects of the HFD, significantly increasing muscle p-AMPK as well as plasma irisin levels. Furthermore, Q upregulated key proteins involved in WAT browning (PR domain containing 16 (PRDM16), PGC-1α, PPARɣ and UCP-1) and mitigated HFD-induced iWAT mass gain and hypertrophy. To further investigate the effects of Q on the FNDC5/irisin pathway, L6 myotubes were stimulated with palmitate. Q (1 μM) prevented palmitate-induced decreased levels of p-AMPK and FNDC5, and cell media secreted irisin. Moreover, Q prevented palmitate-mediated decreased Pgc1α and Fndc5 mRNA levels. Transfecting L6 myotubes with Pgc-1α siRNA revealed that Pgc-1α was involved in Q-mediated upregulation of FNDC5. Overall, results show that Q could attenuate HFD-induced iWAT hypertrophy partly through the upregulation of the FNDC5/irisin pathway in muscle and promoting WAT browning. Consumption of Q-rich foods may help mitigate adiposity associated with the consumption of diets rich in saturated fats.