Celastrol targets CKB-mediated futile creatine cycle in human brown adipocytes thermogenesis

Jingyi Ni , Baicheng Wang , Xinyue Liu , Rui Yin , Jinlin Tang , Siyu Hua , Xiaoxiao Zhang , Yangyang Wu , Shihu Zhang , Chenbo Ji
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Abstract

Celastrol is widely recognized as one of the most potent anti-obesity agents, and its ability to promote adipocyte thermogenesis is thought to be a key mechanism. However, the precise molecular targets through which celastrol modulates thermogenesis in human adipocytes remain unclear. In this study, we synthesized a celastrol-based small molecular probe and employed a combination of photoaffinity labeling (PAL), click chemistry, and Surface Plasmon Resonance (SPR) to identify its direct binding targets. Our results reveal that celastrol directly interacts with creatine kinase B-type (CKB), leading to an increase in CKB protein stability. This suggests that celastrol modulates the futile creatine cycle within human brown adipocytes, thereby contributing to thermogenesis. Collectively, our findings provide new insights into the molecular mechanisms by which celastrol promotes thermogenesis in human brown adipocytes. Notably, we demonstrated that celastrol targets CKB-mediated futile creatine cycle for the first time. These findings not only deepen our understanding of celastrol's role in weight loss but also provides a potential strategy for obesity treatment.
Celastrol 在人类棕色脂肪细胞产热过程中靶向 CKB 介导的徒劳肌酸循环
Celastrol被广泛认为是最有效的抗肥胖药物之一,其促进脂肪细胞产热的能力被认为是一个关键的机制。然而,celastrol调节人体脂肪细胞产热的精确分子靶点尚不清楚。在本研究中,我们合成了一种基于celastrol的小分子探针,并结合光亲和标记(PAL)、点击化学和表面等离子体共振(SPR)来鉴定其直接结合靶点。我们的研究结果表明,雷公藤红素直接与肌酸激酶b型(CKB)相互作用,导致CKB蛋白稳定性增加。这表明,celastrol调节人体棕色脂肪细胞内无用的肌酸循环,从而促进产热。总的来说,我们的发现为雷公藤红素促进人类棕色脂肪细胞产热的分子机制提供了新的见解。值得注意的是,我们首次证明了celastrol靶向ckb介导的无效肌酸循环。这些发现不仅加深了我们对celastrol在减肥中的作用的理解,而且为肥胖治疗提供了潜在的策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Metabolism open
Metabolism open Agricultural and Biological Sciences (General), Endocrinology, Endocrinology, Diabetes and Metabolism
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