SIRT7 regulates lipogenesis in adipocytes through deacetylation of PPARγ2

Aims/Introduction Peroxisome proliferator-activated receptor (PPAR)-gamma 2 is a transcription factor crucial for regulating adipogenesis and glucose/lipid metabolism, and synthetic PPAR gamma ligands, such as thiazolidinediones, are effective oral medication for type 2 diabetes. Sirtuin 7 (SIRT7), a nicotinamide adenine dinucleotide-dependent deacetylase, also controls metabolism. However, it is not known whether SIRT7 regulates the function of PPAR gamma 2 by its deacetylation. Materials and Methods Physical interaction between SIRT7 and PPAR gamma 2, the effect of SIRT7 on PPAR gamma 2 acetylation, and the deacetylation residue targeted by SIRT7 were investigated. The effects of PPAR gamma 2 K382 acetylation on lipid accumulation, gene expression in C3H10T1/2 cell-derived adipocytes, and ligand-dependent transactivation activity were also evaluated. Results We demonstrated that SIRT7 binds to PPAR gamma 2 and deacetylates PPAR gamma 2 at K382. C3H10T1/2-derived adipocytes expressing PPAR gamma 2(K382Q) (a mimic of acetylated K) accumulated much less fat than adipocytes expressing wild-type PPAR gamma 2 or PPAR gamma 2(K382R) (a mimic of nonacetylated K). Global gene expression analysis of adipocytes expressing PPAR gamma 2(K382Q) revealed that K382Q caused the dysregulation of a set of genes involved in lipogenesis, including Srebp1c, Acaca, Fasn, and Scd1. The rosiglitazone-dependent transcriptional activity of PPAR gamma 2(K382Q) was reduced compared with that of PPAR gamma 2(K382R). Conclusion Our findings indicate that SIRT7-dependent PPAR gamma 2 deacetylation at K382 controls lipogenesis in adipocytes.