Impaired Plakophilin-2 in obesity breaks cell cycle dynamics to breed adipocyte senescence

Plakophilin-2 (PKP2) is a key component of desmosomes, which, when defective, is known to promote the fibro-fatty infiltration of heart muscle. Less attention has been given to its role in adipose tissue. We report here that levels of PKP2 steadily increase during fat cell differentiation, and are compromised if adipocytes are exposed to a pro-inflammatory milieu. Accordingly, expression of PKP2 in subcutaneous adipose tissue diminishes in patients with obesity, and normalizes upon mild-to-intense weight loss. We further show defective PKP2 in adipocytes to break cell cycle dynamics and yield premature senescence, a key rheostat for stress-induced adipose tissue dysfunction. Conversely, restoring PKP2 in inflamed adipocytes rewires E2F signaling towards the re-activation of cell cycle and decreased senescence. Our findings connect the expression of PKP2 in fat cells to the physiopathology of obesity, as well as uncover a previously unknown defect in cell cycle and adipocyte senescence due to impaired PKP2. Plakophilin-2 is a key component of desmosomes required to maintain cardiac tissue cohesion. Here the authors uncover a previously unknown defect in cell cycle and adipocyte senescence due to impaired Plakophilin-2 in subjects with obesity.

Automated summary

This study reveals that levels of Plakophilin-2 (PKP2) steadily increase during fat cell differentiation, but are compromised in the presence of inflammation. Expression of PKP2 in subcutaneous adipose tissue diminishes in patients with obesity and normalizes upon weight loss. The impaired PKP2 leads to cell cycle dysfunction and premature senescence in adipocytes.