SREBP1c-PARP1 axis tunes anti-senescence activity of adipocytes and ameliorates metabolic imbalance in obesity

Emerging evidence indicates that the accretion of senescent cells is linked to metabolic disorders. However, the underlying mechanisms and metabolic consequences of cellular senescence in obesity remain obscure. In this study, we found that obese adipocytes are senescence-susceptible cells accompanied with genome instability. Additionally, we discovered that SREBP1c may play a key role in genome stability and senescence in adipocytes by modulating DNA-damage responses. Unexpectedly, SREBP1c interacted with PARP1 and potentiated PARP1 activity during DNA repair, independent of its canonical lipogenic function. The genetic depletion of SREBP1c accelerated adipocyte senescence, leading to immune cell recruitment into obese adipose tissue. These deleterious effects provoked unhealthy adipose tissue remodeling and insulin resistance in obesity. In contrast, the elimination of senescent adipocytes alleviated adipose tissue inflammation and improved insulin resistance. These findings revealed distinctive roles of SREBP1c-PARP1 axis in the regulation of adipocyte senescence and will help decipher the metabolic significance of senescence in obesity. [Display omitted] •Adipocytes are susceptible to genome instability and cellular senescence in obesity•SREBP1c facilitates DNA repair by regulating PARP1 activity, independent of lipogenesis•SREBP1c deficiency accelerates adipocyte senescence via genome instability•SREBP1c deficiency aggravates adipose inflammation and systemic insulin resistance Lee et al. show that adipocytes are vulnerable to cellular senescence in obesity. The accumulation of senescent adipocytes is crucial to provoke the pathological remodeling of adipose tissue and energy imbalance in obesity. They suggest that SREBP1c plays key roles in regulating adipocyte senescence by facilitating PARP1-mediated DNA repair process.