Obesity and hyperinsulinemia drive adipocytes to activate a cell cycle program and senesce

Obesity is considered an important factor for many chronic diseases, including diabetes, cardiovascular disease and cancer. The expansion of adipose tissue in obesity is due to an increase in both adipocyte progenitor differentiation and mature adipocyte cell size. Adipocytes, however, are thought to be unable to divide or enter cell cycle. We demonstrate that mature human adipocytes unexpectedly display a gene and protein signature of cell cycle re-entry. Adipocyte cell cycle progression associates with obesity and hyperinsulinemia, with a concomitant increase in cell size, nuclear size and nuclear DNA content. However, chronic hyperinsulinemia in vitro or in patients, is associated with subsequent cell cycle exit, leading to a premature senescent transcriptomic and secretory profile in adipocytes. Premature senescence is rapidly becoming recognized as an important mediator of stress-induced tissue dysfunction. By demonstrating that adipocytes can re-enter cell cycle we define a mechanism for how mature, human adipocytes senesce and demonstrate that by targeting the adipocyte cell cycle program it is possible to impact adipocyte senescence and obesity-associated adipose tissue inflammation.EGA study EGAS00001005770