Blocking YY1 in adipocytes decouples thermogenic capacity from metabolic benefits by generating spermidine

ABSTRACT: Traditional ideas hold that the accumulation of mitochondria in thermogenic adipose tissue, namely brown and beige fat, helps to increase energy expenditure (EE), thereby alleviating obesity and metabolic disorders. However, recent studies in mice have shown that knocking out key proteins that maintain mitochondrial function can inhibit the activation of thermogenic fat while somehow protecting the mice from high-fat diet (HFD)–induced metabolic disorders. Therefore, the specific role of adipose mitochondria in metabolic benefits needs further analysis. Here, our use of non-biased sequencing-based screening identified YY1 as a key player in maintaining mitochondrial function in thermogenic adipose tissue. YY1 promotes the transcription of electron transport chain (ETC) genes during thermogenesis; thus, YY1 adipose knockout (YAKO) mice showed reduced body temperature and EE under cold stress. Interestingly, YAKO mice showed alleviation of HFD-induced obesity and insulin resistance, which can be attributed to a repression of adipose tissue inflammation. Metabolomic analysis revealed that blocking YY1 in adipocytes directs glucose metabolism toward lactate, enhances the uptake of glutamine, and promotes the production of anti-inflammatory spermidine. Blocking spermidine production can reverse the beneficial metabolic effects observed in YAKO mice. In summary, our findings reveal a metabolic reprogramming pathway centered on adipose mitochondria; that is, although blocking YY1 reduced the mitochondria content, it generated spermidine and alleviated adipose inflammation, therefore leads to a thermogenic capacity-metabolic benefits uncoupling phenomenon.

ORGANISM(S): Mus musculus

PROVIDER: GSE272637 | GEO | 2024/08/26

REPOSITORIES: GEO