Liensinine inhibits beige adipocytes recovering to white adipocytes through blocking mitophagy flux in vitro and in vivo

Abstract

Promoting white-to-beige adipocyte transition is a promising approach for obesity treatment. Although Liensinine (Lie), a kind of isoquinoline alkaloid, has been reported to affect white-to-beige adipocyte transition, its effects on inhibiting beige adipocytes recovering to white adipocytes and maintaining the characteristics of beige adipocyte remain unclear. Therefore, we explored the effects and underlying mechanism of Lie on beige adipocyte maintenance in vitro and in vivo. Here, we first demonstrated that after white adipocytes turned to beige adipocytes by rosiglitazone (Rosi) stimuli, beige adipocytes gradually lost their characteristics and returned to white adipocytes again once Rosi was withdrawn. We found that Lie retained high levels of uncoupling protein 1 (UCP1) and mitochondrial oxidative phosphorylation complex I, II, III, IV and V (COX I–V), oxygen consumption rate (OCR) after Rosi withdrawal. In addition, after Rosi withdrawal, the beige-to-white adipocyte transition was coupled to mitophagy, while Lie inhibited mitophagy flux by promoting the accumulation of pro-cathepsin B (pro-CTSB), pro-cathepsin D (pro-CTSD) and pro-cathepsin L (pro-CTSL), ultimately maintaining the beige adipocytes characteristics in vitro. Moreover, through blocking mitophagy flux, Lie significantly retained the molecular characteristics of beige adipocyte, reduced body weight gain rate and enhanced energy expenditure after stimuli withdrawal in vivo. Together, our data showed that Lie inhibited lysosomal cathepsin activity by promoting the accumulation of pro-CTSB, pro-CTSD and pro-CTSL, which subsequently inhibited mitophagy flux, and ultimately inhibited the beige adipocytes recovering to white adipocytes and maintained the characteristics of beige adipocyte after stimuli withdrawal. In conclusion, by blocking lysosome-mediated mitophagy, Lie inhibits beige adipocytes recovering to white adipocytes and may be a potential candidate for preventing high fat diet induced obesity.