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Fat-targeted small molecule alleviates abnormal adipose tissue remodeling in obesity via SIRT3-driven mitophagy and
Kegang Linghu1, Longkun Hu2, Yu-E Wang3,1
1State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Guizhou Medical University, Guiyang, 550025, Guizhou, China.
Background:
In obesity, excessive energy intake and the expansion of adipose tissue increase ROS generation, contributing to adipocyte dysfunction and inflammation, which leads to abnormal adipose tissue remodeling (ATR). Alpha lipoamide (ALM) is the neutral amide form of lipoic acid, a natural antioxidant extracted from plant-based foods such as asparagus, spinach, and broccoli. This work focuses on ALM's beneficial effects and mechanism in adipose tissue inflammation (ATI) and abnormal ATR in obesity.
Methods:
The anti-inflammatory effect of ALM was evaluated by ELISA, flow cytometry, Western blots, and immunofluorescence assays. The binding affinity of ALM to SIRT3 deacetylase was evaluated through cellular thermal shift assay (CETSA) and molecular docking. The adipose tissue-targeting alpha lipoamide nanoemulsion (ALM-NE) was validated using small animal live imaging. Adipose tissue inflammation was evaluated by histological analysis and immunohistochemical staining in both high-fat diet (HFD) and LPS plus ATP-induced inflammation models in mice.
Results:
ALM suppressed the activation of NLRP3 inflammasome via enhancing SIRT3-mediated autophagy. Co-immunoprecipitation revealed that ALM blunted mitochondrial damage through SIRT3-mediated SOD2 deacetylation and FUNDC1-mediated mitophagy activation, resulting in ROS reduction and NLRP3 inflammasome inactivation. Moreover, ALM mitigates inflammatory crosstalk between macrophages and adipocytes in an in vitro co-culture model. Finally, we established an adipose tissue-targeting ALM-NE, which alleviated ATI in LPS and ATP-induced acute inflammation in mice and inhibited abnormal ATR in high-fat diet-induced obese mice.
Conclusion:
In summary, ALM attenuates inflammatory crosstalk between M1 macrophages and adipocytes by enhancing SIRT3-mediated mitophagy and suppressing NLRP3 inflammasome activation, thereby alleviating adipose tissue inflammation and pathological remodeling in obesity. Thus, ALM has the capacity to become a therapeutic candidate for treating obesity and its associated metabolic disorders.
