Impaired Plakophilin-2 in obesity breaks cell cycle dynamics to breed adipocyte senescence.
Aina LluchJessica LatorreAngela Serena MaioneIsabel EspadasEstefanía Caballano-InfantesJosé Maria Moreno-NavarreteNúria Oliveras-CañellasWifredo RicartMaría M MalagónAlejandro Martín-MontalvoWalter BirchmeierWitold SzymanskiJohannes GraumannMaría Gomez-SerranoElena SommarivaJosé Manuel Fernandez RealFrancisco José OrtegaPublished in: Nature communications (2023)
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.
Keyphrases
- cell cycle
- adipose tissue
- insulin resistance
- stress induced
- weight loss
- cell proliferation
- high fat diet induced
- high fat diet
- dna damage
- poor prognosis
- metabolic syndrome
- endothelial cells
- bariatric surgery
- type diabetes
- weight gain
- skeletal muscle
- roux en y gastric bypass
- heart failure
- glycemic control
- binding protein
- working memory
- long non coding rna
- fatty acid
- cell cycle arrest