Abstract
Obesity results from numerous, interacting genetic, behavioral, and physiological factors. Adipogenesis is partially regulated by several adipocyte-selective microRNAs (miRNAs) and transcription factors that regulate proliferation and differentiation of human adipose-derived mesenchymal stem cells (hMSCs-Ad). In this study, we examined the roles of adipocyte-selective miRNAs in the differentiation of hMSCs-Ad to adipocytes. Results showed that the levels of miR-148a, miR-26b, miR-30, and miR-199a increased in differentiating hMSCs-Ad. Among these miRNAs, miR-148a exhibited significant effects on increasing PPRE luciferase activity (it represents PPAR-dependent transcription, a major factor in adipogenesis) than others. Furthermore, miR-148a expression levels increased in adipose tissues from obese people and mice fed high-fat diet. miR-148a acted by suppressing its target gene, Wnt1, an endogenous inhibitor of adipogenesis. Ectopic expression of miR-148a accelerated differentiation and partially rescued Wnt1-mediated inhibition of adipogenesis. Knockdown of miR-148a also inhibited adipogenesis. Analysis of the upstream region of miR-148a locus identified a 3 kb region containing a functional cAMP-response element-binding protein (CREB) required for miR-148a expression in hMSCs-Ad. The results suggest that miR-148a is a biomarker of obesity in human subjects and mouse model, which represents a CREB-modulated miRNA that acts to repress Wnt1, thereby promoting adipocyte differentiation.
Highlights
MiR-148a is Associated with Obesity and Modulates Adipocyte Differentiation of Mesenchymal Stem Cells through Wnt Signaling
As a step to identifying factors that modulate this process, we examined the roles of microRNAs in adipogenesis because of their functions in a tissueand cell type-specific manner, as well as their essential roles in many biological processes, including differentiation, proliferation, apoptosis, and development11. miR-125b, miR-22, miR-21, and miR-196a maintain the balance between adipocyte and osteogenic differentiation in hMSCs-Ad12–16, whereas miR-817 and miR-14318 positively and miR-27a/b19,20 and let-721 negatively regulate adipogenesis. miRNAs are useful as disease biomarkers and therapeutic targets because of their stability[22]
To identify the miRNAs related to adipogenesis, hMSCs-Ad and adipocytes were analyzed for miRNA expression by miRNA microarray, and more miRNAs changed by at least twofold (P, 0.01) (Fig. 1A; partial data of microarray). miR-148a and miR-26b were highly expressed in differentiated hMSCs-Ad by over fivefold compared with undifferentiated hMSCs-Ad. miR-30 and miR-199a-3p were highly expressed threefold in differentiated hMSCs-Ad compared with undifferentiated hMSCs-Ad
Summary
MiR-148a is Associated with Obesity and Modulates Adipocyte Differentiation of Mesenchymal Stem Cells through Wnt Signaling. Adipogenesis is partially regulated by several adipocyte-selective microRNAs (miRNAs) and transcription factors that regulate proliferation and differentiation of human adipose-derived mesenchymal stem cells (hMSCs-Ad). Analysis of the upstream region of miR-148a locus identified a 3 kb region containing a functional cAMP-response element-binding protein (CREB) required for miR-148a expression in hMSCs-Ad. The results suggest that miR-148a is a biomarker of obesity in human subjects and mouse model, which represents a CREB-modulated miRNA that acts to repress Wnt[1], thereby promoting adipocyte differentiation. Adipocyte differentiation is a highly regulated process that involves sequential activation of several transcription factors, including CEBPa, CEBPb, and PPARc6, as well as cAMP-response element-binding protein (CREB), which has been implicated as an early regulator of the adipocyte differentiation transcriptional program[7] The activities of these transcription factors are partially coordinated by Wnt signaling, which is involved in self-renewal and differentiation of stem cells[8]. The mechanism of new obesity-specific miRNA in this process has not been definitively linked to specific aspects of the hMSCs-Ad differentiation program and transcription factors that regulate miRNA transcription and adipogenesis
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