SIRT7 Inhibits Adipose Tissue Browning Through Deacetylation of PPARγ2 at K382

Adipose tissue (AT) browning is an inducible cellular phenomenon that promotes lipid oxidation to increase energy expenditure, reducing adiposity. Various transcription regulators involved in the AT browning process have been reported, but their complex molecular mechanisms remain poorly understood. Here, we explore the effects of SIRT7, one of seven mammalian sirtuins, on AT browning and elucidate the underlying mechanisms. SIRT7 deficiency increased the expression of browning genes in beige adipocytes differentiated from subcutaneous white AT (scWAT) stromal vascular fraction (SVF) cells isolated from adipocyte-specific Sirt7 knockout (Sirt7 AdKO) mice. The effect of SIRT7 on beige adipocyte differentiation was confirmed in Sirt7 knockdown (KD) mouse scWAT and human supraclavicular brown AT (scBAT) SVF cell lines. Mechanistically, SIRT7 deacetylated PPARγ2 (peroxisome proliferator-activated receptor γ2) at lysine (K) 382, thereby attenuating interaction with the transcriptional coactivator PRDM16 (PR domain-containing 16). In differentiated beige adipocytes, the acetylation-mimicking mutant PPARγ2^K382Q had higher transcriptional activity compared with the deacetylation-mimicking mutant PPARγ2^K382R. Furthermore, the interaction between endogenous SIRT7 and PPARγ2 decreased at the onset of beige adipocyte differentiation. Our findings reveal that SIRT7 is an important thermogenic regulator that puts the brake on AT browning by deacetylating PPARγ2.