Miquelianin, a main functional flavonoid of lotus leaf, induces thermogenic signature via p38‐PINK1‐PARKIN‐mediated mitophagy and mimicking NRF2 signaling during brown adipocyte differentiation

Abstract Adipocytes thermogenesis is an important mechanism for increasing energy expenditure. Here, screening of thermogenic activators (Sirt1 and Ucp1) investigated in C 3 H 10 T 1/2 cells revealed ethanol extract of lotus leaf (LLE) may exert higher activity compared with that of the other 11 ingredients. UPLC‐MS/MS analysis showed that miquelianin was identified as the main flavonoid compounds in LLE (12.8%) and therefore deserves further investigation. The results in C 3 H 10 T 1/2 cells revealed miquelianin promoted lipolysis, enhanced thermogenic programming (Sirt1, Ppargc1a, Prdm16, Cox7a, Nrf1, Cox2, and Ucp1), and induced brown‐like adipocyte formation (Fgf21, Cd137, Tmem26, Tbx1, Cd40, and Cited1). Moreover, miquelianin increased mitochondrial abundance, mitochondrial membrane potential, and NAD + /NADH ratio, suggesting its potential in mitochondria activity. We also observed that miquelianin improved mitochondrial quality by the establishment of mitochondrial dynamics (Mfn1, Mfn2, Opa1, Drp1, and Fis1) and subsequent suppression of autophagy. Chemical inhibition experiment revealed miquelianin may trigger browning via p38‐PINK1‐PARKIN‐mediated mitophagy. Furthermore, in ML385‐treated cells, NRF2, HMOX1, TFAM, and UCP1 were compromised by miquelianin treatment, suggesting that NRF2 signaling is necessary during miquelianin‐induced mitochondria biogenesis. Together, our findings demonstrate that miquelianin may induce browning and mitochondria thermogenic programing by suppressing mitophagy via p38‐PINK1‐PARKIN and mimicking NRF2 signaling.