Zhou Qing, Lu Zongshi, Wang Bowen, Wang Yuyan, Li Li, You Mei, Wang Lijuan, Cao Tingbing, Tong Dan, Xiang Jie, 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.
Int J Biol Sci. 2025 May 15;21(8):3444-3460. doi: 10.7150/ijbs.110741. eCollection 2025.
Endothelial dysfunction and vascular rarefaction are supposed to be secondary to metabolic diseases, while recent evidence has revealed the primary roles of endothelium in initiating and accelerating metabolic disorders. Here, the effects and underlying mechanisms of endothelial SIRT3 in modulating the whitening of BAT during obesity progression were explored. Therefore, mice with global or BAT regional endothelium-specific Sirt3 knockout were constructed and fed with high-fat diet (HFD). The results showed that both global and BAT regional endothelium-specific Sirt3 knockout accelerated diet-induced weight gain, accompanied by glucose intolerance, insulin resistance, and BAT whitening. In vitro results revealed that the inhibition or knockdown of endothelial Sirt3 impeded palmitic acid-induced angiogenesis deficiency, while the overexpression of Sirt3 exhibited the opposite effects. Furtherly, endothelial Sirt3 overexpression ameliorated palmitic acid-induced adipocyte dysfunction and proinflammatory macrophages polarization in a paracrine way. Mechanistically, endothelial SIRT3 deficiency increased the acetylation of fatty acid synthase (FASN), which disturbed the fatty acid metabolism and thus, leading to angiogenesis insufficiency. Moreover, loss of SIRT3 promoted adipocytes dysfunction and proinflammatory macrophage polarization via CASP1-mediated pyroptosis. Endothelial SIRT3 loss contributed to diet-induced BAT whitening and obesity progression and thus, could be a therapeutic target in treating obesity and associated metabolic diseases.
内皮功能障碍和血管稀疏被认为是代谢性疾病的继发表现，而最近的证据揭示了内皮在引发和加速代谢紊乱中的主要作用。在此，研究了内皮细胞SIRT3在肥胖进展过程中调节棕色脂肪组织（BAT）变白的作用及潜在机制。因此，构建了全身或BAT区域内皮特异性Sirt3基因敲除的小鼠，并给予高脂饮食（HFD）。结果表明，全身和BAT区域内皮特异性Sirt3基因敲除均加速了饮食诱导的体重增加，伴有葡萄糖不耐受、胰岛素抵抗和BAT变白。体外实验结果显示，抑制或敲低内皮细胞Sirt3会阻碍棕榈酸诱导的血管生成缺陷，而Sirt3的过表达则表现出相反的效果。此外，内皮细胞Sirt3的过表达以旁分泌方式改善了棕榈酸诱导的脂肪细胞功能障碍和促炎巨噬细胞极化。机制上，内皮细胞SIRT3缺乏会增加脂肪酸合酶（FASN）的乙酰化，从而扰乱脂肪酸代谢，进而导致血管生成不足。此外，SIRT3的缺失通过半胱天冬酶-1（CASP1）介导的细胞焦亡促进脂肪细胞功能障碍和促炎巨噬细胞极化。内皮细胞SIRT3的缺失导致饮食诱导的BAT变白和肥胖进展，因此可能是治疗肥胖及相关代谢性疾病的一个治疗靶点。
