Zhou Qing, Wang Yuyan, Lu Zongshi, Wang Bowen, Li Li, You Mei, Wang Lijuan, Cao Tingbing, Zhao Yu, Li Qiang, Mou Aidi, Shu Wentao, He Hongbo, Zhao Zhigang, Liu Daoyan, Zhu Zhiming, Gao Peng, Yan Zhencheng
Department of Hypertension and Endocrinology, Center for Hypertension and Metabolic Diseases, Daping Hospital, Army Medical University, and Chongqing Institute of Hypertension, Chongqing, China.
School of Medicine, Chongqing University, Chongqing, China.
Obesity (Silver Spring). 2023 Apr;31(4):1050-1063. doi: 10.1002/oby.23707. Epub 2023 Mar 9.
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.
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.
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.
This study emphasizes an important preventive role of SIRT3 in macrophage polarization and implies that SIRT3 is a promising therapeutic target for obesity.
代谢重编程是促炎巨噬细胞极化的主要特征，该过程会导致功能失调的脂肪组织发生炎症。因此，本研究旨在探讨线粒体去乙酰化酶沉默调节蛋白3（SIRT3）是否参与这一病理生理过程。
用高脂饮食处理巨噬细胞特异性Sirt3基因敲除（Sirt3-MKO）小鼠和野生型同窝小鼠。评估体重、葡萄糖耐量和炎症情况。用棕榈酸处理骨髓来源的巨噬细胞和RAW264.7细胞，以探究SIRT3对炎症的作用机制。
在高脂饮食喂养的小鼠的骨髓来源巨噬细胞和脂肪组织巨噬细胞中，SIRT3的表达均显著受到抑制。Sirt3-MKO小鼠体重增加加速且炎症严重，同时能量消耗减少，葡萄糖代谢恶化。体外实验表明，抑制或敲低SIRT3会加剧棕榈酸诱导的促炎巨噬细胞极化，而恢复SIRT3则表现出相反的效果。机制上，SIRT3缺乏导致琥珀酸脱氢酶超乙酰化，进而导致琥珀酸积累，通过增加其启动子上的组蛋白甲基化来抑制 Kruppel样因子4的转录，从而引发促炎巨噬细胞。
本研究强调了SIRT3在巨噬细胞极化中的重要预防作用，并表明SIRT3是肥胖症一个有前景的治疗靶点。
