Docosahexaenoic acid (DHA) inhibits abdominal fat accumulation by promoting adipocyte apoptosis through PPARγ-LC3-BNIP3 pathway-mediated mitophagy

Obesity has always been an overwhelming health concern worldwide. Docosahexaenoic acid (DHA) reduces abdominal fat accumulation by inducing adipocyte apoptosis, but the underlying mechanism remains unclear. Mitophagy, the process of maintaining mitochondrial homeostasis, has a double-edged sword effect that positively or negatively regulates apoptosis. In this study, grass carp (Ctenopharyngodon idellus) was used as an animal model to investigate the role of mitophagy in regulating apoptosis and the potential molecular mechanisms for DHA-induced mitophagy in vivo and in vitro. Firstly, we found that DHA induced the intrinsic apoptosis in grass carp adipocytes, accompanying by activating BNIP3/NIX-mediated mitophagy. Then, suppression of mitophagy alleviated apoptosis and eliminated the inhibition of lipid accumulation induced by DHA in vivo and in vitro. Mechanistically, the DHA-induced mitophagy was caused by activating PPAR gamma and its DNA binding capacity to the LC3 promoter, which promoted the interaction of BNIP3 (rather than NIX) with LC3. However, the inhibition of PPAR gamma in vitro significantly decreased the expression of autophagy-related genes (P < 0.05), reducing the colocalization of mitochondria and lysosomes while preventing BNIP3/NIX-mediated mitophagy-mediated apoptosis and subsequently alleviating the inhibition of lipid accumulation in adipocytes induced by DHA. For the first time, we demonstrated that DHA activates mitophagy by regulating the PPAR gamma-LC3-BNIP3 pathway, consequently inducing apoptosis, which decreases adipocytes, inhibiting lipid accumulation in grass carp. These findings provide new insight into the mechanism of DHA-induced apoptosis mediated by mitophagy as the potential therapeutic target of inhibiting abdominal fat accumulation in vertebrates.

Automated summary

This study investigated the mechanism of docosahexaenoic acid (DHA)-induced apoptosis mediated by mitophagy, using grass carp as an animal model. The results showed that inhibition of mitophagy alleviated apoptosis and eliminated the inhibition of lipid accumulation induced by DHA. Mechanistically, DHA induced mitophagy by activating the PPAR gamma-LC3-BNIP3 pathway. Inhibition of PPAR gamma decreased autophagy-related gene expression and prevented BNIP3/NIX-mediated mitophagy-induced apoptosis, thereby alleviating the inhibition of lipid accumulation.