Blocking adipocyte YY1 decouples thermogenesis from beneficial metabolism by promoting spermidine production.

The accumulation of mitochondria in thermogenic adipose tissue (i.e., brown and beige fat) increases energy expenditure, which can aid in alleviating obesity and metabolic disorders. However, recent studies have shown that knocking out key proteins required to maintain mitochondrial function inhibits the energy expenditure in thermogenic fat, and yet the knockout mice are unexpectedly protected from developing obesity or metabolic disorders when fed a high-fat diet (HFD). In the present study, non-biased sequencing-based screening revealed the importance of YY1 in the transcription of electron transport chain genes and the enhancement of mitochondrial function in thermogenic adipose tissue. Specifically, adipocyte YY1 null (YAKO) mice showed lower energy expenditure and were intolerant to cold stress. Interestingly, YAKO mice showed alleviation of HFD-induced metabolic disorders, which can be attributed to a suppression of adipose tissue inflammation. Metabolomic analysis revealed that blocking YY1 directed glucose metabolism toward lactate, enhanced the uptake of glutamine, and promoted the production of anti-inflammatory spermidine. Conversely, blocking spermidine production in YAKO mice reversed their resistance to HFD-induced disorders. Thus, although blocking adipocyte YY1 impairs the thermogenesis, it promotes spermidine production and alleviates adipose tissue inflammation, therefore leads to an uncoupling of adipose tissue energy expenditure from HFD-induced metabolic disorders.