Abstract
Neural cell adhesion molecule (NCAM) has recently been found on adult stem cells, but its biological significance remains largely unknown. In this study, we used bone-marrow-derived mesenchymal stem cells (MSCs) from wild-type and NCAM knockout mice to investigate the role of NCAM in adipocyte differentiation. It was demonstrated that NCAM isoforms 180 and 140 but not NCAM-120 are expressed on almost all wild-type MSCs. Upon adipogenic induction, Ncam(-/-) MSCs exhibited a marked decrease in adipocyte differentiation compared with wild-type cells. The role of NCAM in adipocyte differentiation was also confirmed in NCAM-silenced preadipocyte 3T3-L1 cells, which also had a phenotype with reduced adipogenic potential. In addition, we found that Ncam(-/-) MSCs appeared to be insulin resistant, as shown by their impaired insulin signaling cascade, such as the activation of the insulin-IGF-1 receptor, PI3K-Akt and CREB pathways. The PI3K-Akt inhibitor, LY294002, completely blocked adipocyte differentiation of MSCs, unveiling that the reduced adipogenic potential of Ncam(-/-) MSCs is due to insulin resistance as a result of loss of NCAM function. Furthermore, insulin resistance of Ncam(-/-) MSCs was shown to be associated with induction of tumor necrosis factor α (TNF-α), a key mediator of insulin resistance. Finally, we demonstrated that re-expression of NCAM-180, but not NCAM-140, inhibits induction of TNF-α and thereby improves insulin resistance and adipogenic potential of Ncam(-/-) MSCs. Our results suggest a novel role of NCAM in promoting insulin signaling and adipocyte differentiation of adult stem cells. These findings raise the possibility of using NCAM intervention to improve insulin resistance.
Highlights
The neural cell adhesion molecule (NCAM), known as CD56, belongs to the immunoglobulin superfamily (Jorgensen and Bock, 1974; Rutishauser et al, 1976)
NCAM deficiency impairs adipocyte differentiation of mouse mesenchymal stem cells (MSCs) in vitro It is well known that MSCs possess multipotency, defined by the ability to differentiate into adipocytes, osteoblasts and chondrocytes (Nagai et al, 2007)
Western blot analysis demonstrated that only NCAM-140 and NCAM-180 were expressed in wild-type MSCs, whereas NCAM-120 expression was not detected under our experimental conditions
Summary
The neural cell adhesion molecule (NCAM), known as CD56, belongs to the immunoglobulin superfamily (Jorgensen and Bock, 1974; Rutishauser et al, 1976). Expressed on neural cells of the central and peripheral nervous system (Schmid et al, 1999), NCAM has been implicated in neurite outgrowth, cell–cell adhesion, synaptic plasticity, learning and memory (Angata et al, 2004; Eckhardt et al, 2000; Weinhold et al, 2005). The three major isoforms of NCAM are NCAM-120, NCAM-140 and NCAM-180, each named according to their apparent molecular masses. These three isoforms share similar extracellular domain, but NCAM-120 lacks a transmembrane domain and is linked to the membrane via a glycosylphosphatidylinositol anchor (Cavallaro and Christofori, 2004). The NCAM-120 isoform is expressed in normal and well differentiated tissues, and the other two isoforms are found predominantly in less differentiated cell types (Jensen and Berthold, 2007)
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