Epigenetic and transcriptional control of adipocyte function by centenarian-associated SIRT6 N308K/A313S mutant

ABSTRACT: Obesity is a major health burden. Adipogenesis, the proliferation and differentiation of pree-adipocytes in mature adipocytes, could be a potential therapeutic approach for obesity. Deficiency of SIRT6, a member of the sirtuin family of nicotinamide adenine dinucleotide (NAD)+-dependent protein deacetylases, blocks adipogenesis. New allelic variants of SIRT6 (N308K/A313S) were recently associated with the longevity in Ashkenazi Jews. In this study, we aimed to clarify how these new centenarian-associated SIRT6 genetic variants affect adipogenesis at the transcriptional and epigenetic level. Overexpression of centenarian-associated SIRT6 mutant increased adipogenic differentiation to a similar extent compared to the WT form. However, it triggered distinct histone PTM profiles in mature adipocytes, with significantly higher acetylation levels, and activated divergent transcriptional programs, including those dependent on signaling related to the sympathetic innervation and to PI3K pathway. 3T3-L1 mature adipocytes overexpressing SIRT6 N308K/A313S displayed increased insulin sensitivity in a neuropeptide Y (NPY)-dependent manner.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Fat Cell

DISEASE(S): Obesity

SUBMITTER: Gabriela Lochmanova  

LAB HEAD: Zbynek Zdrahal

PROVIDER: PXD051761 | Pride | 2024-08-10

REPOSITORIES: Pride