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 (KO) mice are unexpectedly protected from developing obesity or metabolic disorders when fed a high-fat diet (HFD). In the current study, nonbiased sequencing-based screening revealed the importance of Yin Yang 1 (YY1) in the transcription of electron transport chain genes and the enhancement of mitochondrial function in thermogenic adipose tissue. Specifically, YY1 adipocyte-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, alleviates adipose tissue inflammation, and therefore leads to an uncoupling of adipose tissue energy expenditure from HFD-induced metabolic disorders.

Chromatin open atlas profiling in white, beige, and brown adipocytes identified Yin Yang 1 (YY1) as a key transcription factor governing electron transport chain gene expression and mitochondrial function in thermogenic adipocytes. Knocking out adipocyte YY1 leads to impaired thermogenesis under cold stress while protecting the mice from diet-induced obesity and metabolic disorders. YY1-null adipocytes undergo metabolic reprogramming, with increased glutamine use and spermidine generation that combat adipose tissue inflammation and insulin resistance, resulting in an uncoupling of thermogenic capacity and metabolic benefits.