Abstract
The development, homeostasis, or increase of the adipose tissue is driven by the induction of the adipogenic differentiation (adipogenesis) of undifferentiated mesenchymal stem cells (MSCs). Adipogenesis can be inhibited by androgen stimulation of these MSCs resulting in the transcription initiation or repression of androgen receptor (AR) regulated genes. AR not only regulates the transcription of protein-coding genes but also the transcription of several non-coding microRNAs involved in the posttranscriptional gene regulation (herein designated as AndroMiRs). As microRNAs are largely involved in differentiation processes such as adipogenesis, the involvement of AndroMiRs in the androgen-mediated inhibition of adipogenesis is likely, however, not yet intensively studied. In this review, existing knowledge about adipogenesis-related microRNAs and AndroMiRs is summarized, and putative cross-links are drawn, which are still prone to experimental validation.
Highlights
Androgen regulation of gene transcription is mediated through testosterone, or the more bioactive derivate dihydrotestosterone (DHT), or any other androgenic hormone binding to the androgen receptor (AR), followed by intra-nuclear binding of the ligand-activated AR to androgen-responsive elements (ARE) in the promoter region of the respective gene and subsequent transcription initiation or repression by AR-recruited cofactors [1,2]
The expression of the marker gene for adipogenesis, PPARγ, and the marker gene for osteogenesis, Cbfa-1, were both increased after transfection of mesenchymal stem cells (MSCs) with miR-21 mimics, while miR-21 inhibition resulted in a reduced expression level of both genes [23]
Comparing the androgen-regulated microRNAs (AndroMiRs) to the adipogenesis-related microRNAs (AdipoMiRs), several overlapping candidates can be extracted from the existing literature
Summary
Androgen regulation of gene transcription is mediated through testosterone, or the more bioactive derivate dihydrotestosterone (DHT), or any other androgenic hormone binding to the androgen receptor (AR), followed by intra-nuclear binding of the ligand-activated AR to androgen-responsive elements (ARE) in the promoter region of the respective gene and subsequent transcription initiation or repression by AR-recruited cofactors [1,2]. Mei et al demonstrated that through regulating the ERK-MAPK pathway, the only active signaling during adipogenic, osteogenic and chondrogenic differentiation, miR-21 stimulates MSC differentiation on an early stage In this context, the expression of the marker gene for adipogenesis, PPARγ, and the marker gene for osteogenesis, Cbfa-1, were both increased after transfection of MSC with miR-21 mimics, while miR-21 inhibition resulted in a reduced expression level of both genes [23]. Androgen-induced miR-1 downregulates TCF7 in prostate cancer cell lines and negatively impacts the Wnt signaling pathway [96] Another target gene of miR-1, in the context of the transition of PCa from androgen-sensitive to castration-resistant, is ZBTB46 [97]. The AR is regulating the expression of many microRNAs, AR translation is repressed by several microRNAs (an actual overview is given in Table S3), adding an additional regulative layer to the interplay between these two factors in differentiation processes
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