Nck1 Deficiency Impairs Adipogenesis by Activation of PDGFRα in Preadipocytes

Obesity results from an excessive expansion of white adipose tissue (WAT), which is still poorly understood from an etiologic-mechanistic perspective. Here, we report that Nck1, a Src homology domain-containing adaptor, is upregulated during WAT expansion and in vitro adipogenesis. In agreement, Nck1 mRNA correlates positively with peroxisome proliferator-activated receptor (PPAR) γ and adiponectin mRNAs in the WAT of obese humans, whereas Nck1-deficient mice display smaller WAT depots with reduced number of adipocyte precursors and accumulation of extracellular matrix. Furthermore, silencing Nck1 in 3T3-L1 preadipocytes increases the proliferation and expression of genes encoding collagen, whereas it decreases the expression of adipogenic markers and impairs adipogenesis. Silencing Nck1 in 3T3-L1 preadipocytes also promotes the expression of platelet-derived growth factor (PDGF)-A and platelet-derived growth factor receptor (PDGFR) α activation and signaling. Preventing PDGFRα activation using imatinib, or through PDGF-A or PDGFRα deficiency, inhibits collagen expression in Nck1-deficient preadipocytes. Finally, imatinib rescues differentiation of Nck1-deficient preadipocytes. Altogether, our findings reveal that Nck1 modulates WAT development through PDGFRα-dependent remodeling of preadipocytes.