2051-LB: Rhein Targets Macrophage SIRT2 to Promote Adipose Tissue Thermogenesis in Obesity

Introduction & Objective: Rhein, a component derived from rhubarb as well as the active metabolite of the anti-osteoarthritis drug diacerein, has been proven to possess strong anti-inflammatory properties. However, the exact mechanism underlying the anti-inflammatory effects of rhein, and the role of rhein in ameliorating obesity remains unclear. Methods: Diet induced obese (DIO) mice were employed to observe the effects of rhein on metabolism. A macrophage-adipocyte co-culture system was constructed to elucidate the exact mechanism underlying the beneficial effect of rhein on metabolism. Acetylome analysis was performed to screen the acetylation-modifying enzymes regulated by rhein. Surface plasmon resonance assay was used to verify the interaction between rhein and SIRT2. Lyz2-iCre mice injected with rAAV-DIO-shSirt2 were used to verify the durg target of rhein in vivo. PBMCs from patients with obesity receiving diacerein or placebo treatment were collected for acetylation assay. Results: Rhein mitigated obesity by promoting white adipose tissue thermogenesis in DIO mice, and rhein promoted adipocyte thermogenesis through inhibiting the activation of NLRP3 inflammasome in macrophages. Further study proved that rhein directly interacts with SIRT2 and inhibits NLRP3 inflammasome activation in a SIRT2-dependent way. Myeloid knockdown of Sirt2 abrogated the metabolic benefits induced by rhein in DIO mice. PBMCs from patients with obesity receiving diacerein treatment had significant lower level of acetylation than those from the placebo group. Conclusion: Rhein promotes adipose tissue thermogenesis by targeting SIRT2 to regulate acetylation-mediated NLRP3 inflammasome activation in macrophages during obesity. Rhein and its derivatives may become potential drug for treating obesity. Disclosure R. Zhou: None. Z. Zhu: None. P. Xu: None. L. Shen: None. Z. Wang: None. Y. Xue: None. Y. Xiang: None. Y. Cao: None. X. Yu: None. J. Yu: None. J. Zhao: None. J. Yan: None. Q. Yang: None. P. Fang: None. W. Shang: None. Funding National Natural Science Foundation of China (81873060, 81473391 and 82374100); Priority Academic Program Development of Jiangsu Higher Education Institutions (ZYX03KF058); Graduate Research and Innovation Projects of Jiangsu Province (KYCX23_2133 and SJCX23_0728).