Lnk is an important modulator of insulin-like growth factor-1/Akt/peroxisome proliferator-activated receptor-gamma axis during adipogenesis of mesenchymal stem cells

Abstract

Adipogenic differentiation of mesenchymal stem cells (MSCs) is critical for metabolic homeostasis and nutrient signaling during development. However, limited information is available on the pivotal modulators of adipogenic differentiation of MSCs. Adaptor protein Lnk (Src homology 2B3 [SH2B3]), which belongs to a family of SH2-containing proteins, modulates the bioactivities of different stem cells, including hematopoietic stem cells and endothelial progenitor cells. In this study, we investigated whether an interaction between insulin-like growth factor-1 receptor (IGF-1R) and Lnk regulated IGF-1-induced adipogenic differentiation of MSCs. We found that wild-type MSCs showed greater adipogenic differentiation potential than Lnk–/– MSCs. An ex vivo adipogenic differentiation assay showed that Lnk–/– MSCs had decreased adipogenic differentiation potential compared with wild-type MSCs. Interestingly, we found that Lnk formed a complex with IGF-1R and that IGF-1 induced the dissociation of this complex. In addition, we observed that IGF-1-induced increase in the phosphorylation of Akt and mammalian target of rapamycin was triggered by the dissociation of the IGF-1R–Lnk complex. Expression levels of a pivotal transcription factor peroxisome proliferator-activated receptor gamma (PPAR-γ) and its adipogenic target genes (LPL and FABP4) significantly decreased in Lnk–/– MSCs. These results suggested that Lnk adaptor protein regulated the adipogenesis of MSCs through the IGF-1/Akt/PPAR-γ pathway.

Suppression of adipocyte differentiation by low‐intensity pulsed ultrasound via inhibition of insulin signaling and promotion of CCN family protein 2

“…Activation of the PI3K pathway is triggered by the binding of the receptor to insulin receptor substrate, resulting in the generation of phosphatidylinositol‐3, 4, 5‐triphosphate, which leads to activation of Akt by phosphoinositide‐dependent kinases 27 . The phosphorylated Akt is responsible for the regulation of adipogenic genes via mTOR, that is, the mammalian target of rapamycin 28 . On the other hand, in the MAPK pathway, Ras or SOS, which is an adapter protein, activates ERK1/2; and the phosphorylated ERK1/2 causes upregulation of C/EBPβ/σ expression 29 and activation of PPARγ 30 .…”

“…27 The phosphorylated Akt is responsible for the regulation of adipogenic genes via mTOR, that is, the mammalian target of rapamycin. 28 On the other hand, in the MAPK pathway, Ras or SOS, which is an adapter protein, activates ERK1/2; and the phosphorylated ERK1/2 causes upregulation of C/EBPβ/σ expression 29 and activation of PPARγ. 30 Expression/activation of C/EBPα needs the activation of both C/EBPβ/σ 29 and PPARγ.…”

Alveolar Epithelial Cells Promote IGF-1 Production by Alveolar Macrophages Through TGF-β to Suppress Endogenous Inflammatory Signals

“…Lee et al showed that IGF-1 participates in the adipogenesis of mesenchymal stem cells by regulating the expression of PPARγ (48). In addition, IGF-1 induces the proliferation and invasion of UM cells by inhibiting Foxo3a (49).…”

Recent advances of the mammalian target of rapamycin signaling in mesenchymal stem cells

“…Lipid synthesis is a key nutrient metabolic pathway that allows organisms to remain active even when energy is limited ( Caron et al, 2015 ; Wang et al, 2021 ). Adipogenic differentiation of MSCs is a key developmental process associated with metabolic homeostasis and nutritional signal transduction ( Fernandez-Veledo et al, 2013 ; Lee et al, 2016 ). In adipose cells, mTOR plays a central role in protein synthesis and adipose tissue morphogenesis ( Xiang et al, 2011 ).…”