Perilipin 2 modulates adipogenic differentiation of primary dermal fibroblasts and is extracellularly released during adipocyte maturation

Abstract Perilipin 2 (PLIN2) is a lipid droplet (LD)-associated protein broadly expressed across tissues, where it regulates fatty acid uptake, lipid storage, and LD dynamics. During adipogenesis, PLIN2 is localized to small LDs in preadipocytes but is absent in mature adipocytes, where it is replaced by other perilipins. Whether PLIN2 loss represents a driver or a consequence of adipogenic differentiation remains unresolved. To address this question, we performed in vitro and ex vivo analyses. Adipogenic differentiation was induced in human primary dermal fibroblasts (DFs), and PLIN2 function was investigated using small interfering RNA (siRNA)-mediated silencing and treatment with Brefeldin A and Monensin (B + M). In parallel, plasma samples from both physically active healthy subjects and patients with mobility impairment were analyzed to assess PLIN2 expression. PLIN2 silencing accelerated adipogenic differentiation, whereas its higher expression induced by B + M markedly delayed this process. Notably, although Plin2 mRNA became nearly undetectable during differentiation, PLIN2 protein continued to be synthesized and, at variance with DFs, released into the culture supernatant as a circulating form (cPLIN2), partially associated with extracellular vesicles. Consistent with these findings, plasma cPLIN2 levels in vivo positively correlated with increased adiposity and low physical activity. Moreover, skeletal muscle samples from healthy subjects exhibited higher expression of CD36, a recently identified PLIN2 interactor, compared with patients. Collectively, these data identify PLIN2 as a negative regulator of the early phases of adipogenic differentiation and suggest that its secretion may represent a mechanism of interorgan communication potentially mediated by extracellular vesicles.