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

Aina Lluch, Jessica Latorre, Angela Serena-Maione, Isabel Espadas, Estefanía Caballano-Infantes, José M. Moreno-Navarrete, Núria Oliveras-Cañellas, Wifredo Ricart, María M. Malagón, Alejandro Martin-Montalvo, Walter Birchmeier, Witold Szymanski, Johannes Graumann, María Gómez-Serrano, Elena Sommariva, José M. Fernández-Real and Francisco J. Ortega ()
Additional contact information
Aina Lluch: Institut d’Investigació Biomèdica de Girona (IDIBGI)
Jessica Latorre: Institut d’Investigació Biomèdica de Girona (IDIBGI)
Angela Serena-Maione: Centro Cardiologico Monzino IRCCS
Isabel Espadas: University Pablo de Olavide
Estefanía Caballano-Infantes: Institut d’Investigació Biomèdica de Girona (IDIBGI)
José M. Moreno-Navarrete: Institut d’Investigació Biomèdica de Girona (IDIBGI)
Núria Oliveras-Cañellas: Institut d’Investigació Biomèdica de Girona (IDIBGI)
Wifredo Ricart: Institut d’Investigació Biomèdica de Girona (IDIBGI)
María M. Malagón: Instituto de Salud Carlos III (ISCIII)
Alejandro Martin-Montalvo: University Pablo de Olavide
Walter Birchmeier: Max Delbrück Center for Molecular Medicine
Witold Szymanski: Philipps University
Johannes Graumann: Philipps University
María Gómez-Serrano: Philipps University
Elena Sommariva: Centro Cardiologico Monzino IRCCS
José M. Fernández-Real: Institut d’Investigació Biomèdica de Girona (IDIBGI)
Francisco J. Ortega: Institut d’Investigació Biomèdica de Girona (IDIBGI)

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-40596-0

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