Mitochondrial dysfunction caused by SIRT3 inhibition drives proinflammatory macrophage polarization in obesity

作者：Qing Zhou, Yuyan Wang, Zongshi Lu, Bowen Wang, Li Li, Mei You, Lijuan Wang, Tingbing Cao, Yu Zhao, Qiang Li, Aidi Mou, Wentao Shu, Hongbo He, Zhigang Zhao, Daoyan Liu, Zhiming Zhu, Peng Gao, Zhencheng Yan · 发表于：Obesity · 年份：2023 · DOI：10.1002/oby.23707 · 被引用次数：31 · 研究领域：Sirtuins and Resveratrol in Medicine、Immune cells in cancer、Adipokines, Inflammation, and Metabolic Diseases

OBJECTIVE: Metabolic reprogramming is a main feature of proinflammatory macrophage polarization, a process that leads to inflammation in dysfunctional adipose tissue. Therefore, the study aim was to explore whether sirtuin 3 (SIRT3), a mitochondrial deacetylase, participates in this pathophysiological process. METHODS: Macrophage-specific Sirt3 knockout (Sirt3-MKO) mice and wild-type littermates were treated with a high-fat diet. Body weight, glucose tolerance, and inflammation were evaluated. Bone marrow-derived macrophages and RAW264.7 cells were treated with palmitic acid to explore the mechanism of SIRT3 on inflammation. RESULTS: The expression of SIRT3 was significantly repressed in both bone marrow-derived macrophages and adipose tissue macrophages in mice fed with a high-fat diet. Sirt3-MKO mice exhibited accelerated body weight and severe inflammation, accompanied with reduced energy expenditure and worsened glucose metabolism. In vitro experiments showed that SIRT3 inhibition or knockdown exacerbated palmitic acid-induced proinflammatory macrophage polarization, whereas SIRT3 restoration displayed opposite effects. Mechanistically, SIRT3 deficiency resulted in hyperacetylation of succinate dehydrogenase that led to succinate accumulation, which suppressed the transcription of Kruppel-like factor 4 via increasing histone methylation on its promoter, thus evoking proinflammatory macrophages. CONCLUSIONS: This study emphasizes an important preventive role of SIRT3 in ma...