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

Author

Listed:
  • Aina Lluch

    (Institut d’Investigació Biomèdica de Girona (IDIBGI)
    Instituto de Salud Carlos III (ISCIII))

  • Jessica Latorre

    (Institut d’Investigació Biomèdica de Girona (IDIBGI)
    Instituto de Salud Carlos III (ISCIII))

  • Angela Serena-Maione

    (Centro Cardiologico Monzino IRCCS)

  • Isabel Espadas

    (University Pablo de Olavide)

  • Estefanía Caballano-Infantes

    (Institut d’Investigació Biomèdica de Girona (IDIBGI)
    Instituto de Salud Carlos III (ISCIII))

  • José M. Moreno-Navarrete

    (Institut d’Investigació Biomèdica de Girona (IDIBGI)
    Instituto de Salud Carlos III (ISCIII))

  • Núria Oliveras-Cañellas

    (Institut d’Investigació Biomèdica de Girona (IDIBGI)
    Instituto de Salud Carlos III (ISCIII))

  • Wifredo Ricart

    (Institut d’Investigació Biomèdica de Girona (IDIBGI)
    Instituto de Salud Carlos III (ISCIII))

  • María M. Malagón

    (Instituto de Salud Carlos III (ISCIII)
    University of Cordoba, Reina Sofia University Hospital)

  • 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)
    Instituto de Salud Carlos III (ISCIII)
    University of Girona)

  • Francisco J. Ortega

    (Institut d’Investigació Biomèdica de Girona (IDIBGI)
    Instituto de Salud Carlos III (ISCIII))

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.

Suggested Citation

  • 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, 2023. "Impaired Plakophilin-2 in obesity breaks cell cycle dynamics to breed adipocyte senescence," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40596-0
    DOI: 10.1038/s41467-023-40596-0
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    as
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