Mitophagy suppression by miquelianin-rich lotus leaf extract induces 'beiging' of white fat via AMPK/DRP1-PINK1/PARKIN signaling axis

Background: Lotus (Nelumbo nucifera) leaf has been described to have anti-obesity activity, but the role of white fat 'browning' or 'beiging' in its beneficial metabolic actions remains unclear. Here, 3T3-L1 cells and high-fat-diet (HFD)-fed mice were used to evaluate the effects of miquelianin-rich lotus leaf extract (LLE) on white-to-beige fat conversion and its regulatory mechanisms.Results: Treatment with LLE increased mitochondrial abundance, mitochondrial membrane potential and NAD(+)/NADH ratio in 3T3-L1 cells, suggesting its potential in promoting mitochondrial activity. qPCR and/or western blotting analysis confirmed that LLE induced the expression of beige fat-enriched gene signatures (e.g. Sirt1, Cidea, Dio2, Prdm16, Ucp1, Cd40, Cd137, Cited1) and mitochondrial biogenesis-related markers (e.g. Nrf1, Cox2, Cox7a, Tfam) in 3T3-L1 cells and inguinal white adipose tissue of HFD-fed mice. Furthermore, we found that LLE treatment inhibited mitochondrial fission protein DRP1 and blocked mitophagy markers such as PINK1, PARKIN, BECLIN1 and LC-3B. Chemical inhibition experiments revealed that AMPK/DRP1 signaling was required for LLE-induced beige fat formation via suppressing PINK1/PARKIN/mitophagy.Conclusion: Our data reveal a novel mechanism underlying the anti-obesity effect of LLE, namely the induction of white fat beiging via AMPK/DRP1/mitophagy signaling.(c) 2023 Society of Chemical Industry.