miR-148a is Associated with Obesity and Modulates Adipocyte Differentiation of Mesenchymal Stem Cells through Wnt Signaling

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.

miRNA regulation of white and brown adipose tissue differentiation and function

“…WNT signaling has also been demonstrated to be a target for miRNA mediated regulation of adipogenesis. Expression of miR-148 was elevated with obesity in mice and humans, and miR-148a was found to promote adipogenesis and impair WNT-mediated repression of adipogenesis by targeting WNT1 [24]. miR-210 has also been shown to help promote adipocyte differentiation by targeting transcription factor 7 like 2 (Tcf7l2), which acts downstream of WNT signaling [13].…”

Adipogenic miRNA and meta-signature miRNAs involved in human adipocyte differentiation and obesity

“…Additionally, miR-93 and miR-720 were lowly expressed with 5-fold in mature adipocytes compared to SVCs/hMSCs-Ad. Among these differentially expressed miRNAs, our group did further research for the adipogenic miRNAs in vivo and in vitro , including miR-148a [5], miR-26b [10], miR-146b [6] and miR-1275.…”

“…This finding has implicated miR-146b as a positive regulator of accelerated adipocyte differentiation through modulation of SIRT1 and KLF7 [6]. Indeed, our previous study found that miR-148a promotes hMSCs-Ad to differentiate to mature adipocyte by targeting Wnt1 [5]. Additionally, our group [7] has also suggested that inhibited miR-26b inhibits adipogenic differentiation in human preadipocytes, and miR-335, as a potential adipogenic miRNA, is involved in adipose tissue inflammation and is highly expressed in mature 3T3-L1 [21].…”

“…In our previous study, we found that miR-148a, as a biomarker of obesity, promoted adipogenesis by inhibiting Wnt1 [5]. miR-146b as a positive regulator of accelerated adipocyte differentiation through modulation of KLF7 [6].…”

Increased Ocular Levels of MicroRNA-148a in Cases of Retinal Detachment Promote Epithelial–Mesenchymal Transition

“…Ectopic expression of miR-148a reportedly accelerates the differentiation of mesenchymal stem cells through Wnt signaling. 44 Further, cells expressing miR-148a have been shown to produce greater amounts of proteoglycans and collagen, in particular type II collagen, with proteoglycan and collagen secretion into culture medium shown to be inhibited, but total collagen production increased, by miR148a. 45 These corroborating studies indicate that miR-148a has multifunction roles depending on cellular conditions.…”