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Roles of nuclear receptor 4a family in maintenance of stemness of murine adipose-derived stem cells

Obesity is associated with proliferation and differentiation of adipose-derived stem cells (ADSCs) into mature adipocytes. Nutritional stimuli induce ADSCs proliferation and differentiation, and this process is well established because master regulators of adipogenic differentiation, C/EBPalpha and PPARgamma were identified. However, under normal condition, molecular mechanisms to maintain stemness of ADSCs are largely unknown. To identify genes essential for the maintenance, microarray analysis was performed on murine ADSCs and 4-day cultured ADSCs (preadipocytes). Among the 223 up-regulated transcriptional factor genes in ADSCs, we focused on nuclear receptor 4a (Nr4a) family, which play diverse roles including metabolic processes. Nr4a-overexpressed preadipocytes showed reduced accumulation of lipid droplet and decreased expressions of C/EBPalpha and PPARgamma. ChIP analysis confirmed that Nr4a directly bound to C/EBPalpha and PPARgamma promotor. Nr4a family is induced by multiple signals including cyclic AMP in a cell type-specific manner. Application of a cAMP analogue to ADSCs induced Nr4a expressions and decreased expressions of PPARgamma. These data suggested that Nr4a inhibited ADSCs differentiation in a cAMP-dependent manner.