Nature Communications · 17 authors, 9 centres
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This study combines human adipose tissue observations with in vitro experiments on human adipocytes to show that plakophilin-2 (PKP2) expression increases during adipocyte differentiation but is compromised in obesity-associated inflammation, leading to disrupted cell cycle dynamics and premature adipocyte senescence.
PKP2 expression was found to steadily increase during adipogenic differentiation, peaking in terminally differentiated adipocytes. In subcutaneous adipose tissue from patients with obesity, PKP2 levels were decreased and normalized following weight loss. Treatment of human adipocytes with macrophage-conditioned medium mimicking obese adipose tissue inflammation reduced PKP2 expression. Loss-of-function experiments using viral vector and siRNA-mediated knockdown revealed that impaired PKP2 disrupts cell cycle dynamics, alters E2F transcription factor signaling, decreases cyclin D1, and promotes adipocyte senescence marked by increased β-galactosidase activity and H₂O₂ release. Restoration of PKP2 in inflamed adipocytes normalized PKCα subcellular localization, reactivated cell cycle signatures, reduced H₂O₂ extrusion, and decreased senescence.
