Endothelial SIRT3 deficiency predisposes brown adipose tissue to whitening in diet-induced obesity.

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.