Liensinine Inhibits Beige Adipocytes Recovering to white Adipocytes through Blocking Mitophagy Flux In Vitro and In Vivo.

Siyu Xie,Yixuan Li,Wendi Teng,Yuan Li,Baoguo Sun,Min Du

doi:10.3390/nu11071640

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stimuli, beige adipocytes gradually lost their characteristics and returned to white adipocytes again once Rosi was withdrawn.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.

Highlights

Obesity is strongly associated with excessive white adipocytes, and increases the risk of metabolic syndromes or disorders including diabetes, cardiovascular diseases, and multiple types of cancer [1,2,3]. clinical care and various medical studies have been made, approximately 28 million patients worldwide die from obesity each year [3]
Our data showed that Lie inhibited lysosomal cathepsin activity by promoting the accumulation of pro-Cathepsin B (CTSB), pro-Cathepsin D (CTSD) and pro-cathepsin L (CTSL), which subsequently inhibited mitophagy flux, and inhibited the beige adipocytes recovering to white adipocytes and maintained the characteristics of beige adipocyte after stimuli withdrawal
Browning white adipocytes were induced by treating white adipocytes with 10 μM Rosi for 2 days and we defined them as beige adipocytes in the following text (Figure 1A)

Summary

Introduction

Obesity is strongly associated with excessive white adipocytes, and increases the risk of metabolic syndromes or disorders including diabetes, cardiovascular diseases, and multiple types of cancer [1,2,3]. clinical care and various medical studies have been made, approximately 28 million patients worldwide die from obesity each year [3]. Increased active brown adipocytes and beige adipocytes can promote energy expenditure, and so may be potential targets for treating metabolic disorders and obesity [6,7,8]. Brown adipocytes constitutively express high levels of uncoupling protein 1 (UCP1) and increase mitochondria mass [9]. White-to-beige adipocyte transition is coupled to a UCP1 expression increase and mitochondria mass biogenesis. UCP1 can protect mice from high fat diet- (HFD)-induced obesity through improving metabolic rate in mice [12]. By promoting white-to-beige transition, β3-AR agonist helped HFD-induced obesity mice improve their resting metabolic rate. By exploring the mechanism of regulating mitochondria degradation in this situation, the authors found that microphthalmia-associated transcription factor, which modulates mitophagy related protein expression levels, was increased on initiation of the beige-to-white transition [22]

Methods

Results

Conclusion