Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science & Nutritional Engineering, China Agricultural University, Beijing100083, China.
Department of Animal Sciences, Washington State University, Pullman, Washington, WA 99164, USA.
Nutrients. 2019 Jul 18;11(7):1640. doi: 10.3390/nu11071640.
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stimuli, beige adipocytes gradually lost their characteristics and returned to white adipocytes again once Rosi was withdrawn.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.
促进白色脂肪细胞向米色脂肪细胞的转变是治疗肥胖的一种很有前途的方法。虽然莲心碱（Lie）是一种异喹啉生物碱，已被报道影响白色脂肪细胞向米色脂肪细胞的转变，但它对抑制米色脂肪细胞恢复为白色脂肪细胞并维持米色脂肪细胞特征的影响尚不清楚。因此，我们在体外和体内探索了 Lie 对米色脂肪细胞维持的作用和潜在机制。在这里，我们首先证明，在用罗格列酮（Rosi）刺激将白色脂肪细胞转化为米色脂肪细胞后，一旦撤回 Rosi，米色脂肪细胞的特征逐渐丧失，再次恢复为白色脂肪细胞。我们发现，Lie 在撤回 Rosi 后，仍能保持较高水平的解偶联蛋白 1（UCP1）和线粒体氧化磷酸化复合物 I、II、III、IV 和 V（COX I-V），耗氧量（OCR）。此外，在撤回 Rosi 后，米色脂肪细胞向白色脂肪细胞的转变与自噬耦联，而 Lie 通过促进前组织蛋白酶 B（pro-CTSB）、前组织蛋白酶 D（pro-CTSD）和前组织蛋白酶 L（pro-CTSL）的积累来抑制自噬通量，最终维持了体外米色脂肪细胞的特征。此外，通过阻断自噬通量，Lie 显著保留了米色脂肪细胞的分子特征，在体内撤回刺激后降低了体重增长率和增强了能量消耗。综上所述，我们的数据表明，Lie 通过促进 pro-CTSB、pro-CTSD 和 pro-CTSL 的积累来抑制溶酶体组织蛋白酶的活性，从而抑制自噬通量，最终抑制米色脂肪细胞恢复为白色脂肪细胞，并维持撤回刺激后的米色脂肪细胞特征。总之，通过阻断溶酶体介导的自噬，Lie 抑制米色脂肪细胞恢复为白色脂肪细胞，可能是预防高脂肪饮食诱导肥胖的潜在候选药物。
