Rhein targets macrophage SIRT2 to promote adipose tissue thermogenesis in obesity in mice

• Published in: Communications biology Vol. 7; no. 1; pp. 1003 - 14
• Main Authors: Zhou, Ruo-Nan, Zhu, Zi-Wei, Xu, Ping-Yuan, Shen, Li-Xuan, Wang, Ziwei, Xue, Ying-Ying, Xiang, Ying-Ying, Cao, Yue, Yu, Xi-Zhong, Zhao, Juan, Jin, Yu, Yan, Jing, Yang, Qin, Fang, Peng-Hua, Shang, Wen-Bin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.08.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/109; 13/31; 13/51; 13/89; 14/34; 14/35; 14/5; 14/63; 38/47; 59; 631/92/436/108; 64; 64/60; 692/163/2743/393; 692/308/2778; 82; 82/58; 96; Acetylation; Adipocytes; Adipocytes - drug effects; Adipocytes - metabolism; Adipose tissue; Adipose Tissue - drug effects; Adipose Tissue - metabolism; Animals; Anthraquinones - pharmacology; Anti-inflammatory agents; Biomedical and Life Sciences; Body fat; Cell activation; Inflammasomes; Inflammasomes - drug effects; Inflammasomes - metabolism; Inflammation; Life Sciences; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Male; Metabolic rate; Mice; Mice, Inbred C57BL; Molecular modelling; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Obesity; Obesity - drug therapy; Obesity - metabolism; Sirtuin 2 - genetics; Sirtuin 2 - metabolism; Therapeutic targets; Thermogenesis; Thermogenesis - drug effects
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-024-06693-6

Rhein, a component derived from rhubarb, has been proven to possess anti-inflammatory properties. Here, we show that rhein mitigates obesity by promoting adipose tissue thermogenesis in diet-induced obese mice. We construct a macrophage-adipocyte co-culture system and demonstrate that rhein promotes adipocyte thermogenesis through inhibiting NLRP3 inflammasome activation in macrophages. Moreover, clues from acetylome analysis identify SIRT2 as a potential drug target of rhein. We further verify that rhein directly interacts with SIRT2 and inhibits NLRP3 inflammasome activation in a SIRT2-dependent way. Myeloid knockdown of SIRT2 abrogates adipose tissue thermogenesis and metabolic benefits in obese mice induced by rhein. Together, our findings elucidate that rhein inhibits NLRP3 inflammasome activation in macrophages by regulating SIRT2, and thus promotes white adipose tissue thermogenesis during obesity. These findings uncover the molecular mechanism underlying the anti-inflammatory and anti-obesity effects of rhein, and suggest that rhein may become a potential drug for treating obesity. Zhou et al. reveal that rhein improves adipose tissue thermogenesis via suppressing the NLRP3 inflammasome in macrophages during obesity. They further identify that rhein directly binds to SIRT2 and inhibits NLRP3 inflammasome by activating SIRT2.