Investigation of the Curcumin- and Berberine-Mediated Post-Transcriptional Regulation on Ehnancing Brown Adipogenesis

Adipocytes compose prominent tissues that maintain the energy homeostasis of mammals. White adipose tissue (WAT) efficiently reserves the triglyceride as energy source, whereas brown adipose tissue (BAT) expenditures the energy through non-shivering thermogenesis in small rodents and infants. Apart from the function, the knowledge of regulatory mechanism involved in the development of BAT is also sparse. Posttranscriptional regulations, including alternative splicing (AS), mRNA degradation and transport, function as complex and prevalent mechanisms in determining the fate or function of eukaryotic cells. Approximately 95% of human genes generate more than one transcript to expand the genetic diversity through alternative splicing mechanism. The tissue- or stage-specific expression of non-coding RNA, such as microRNAs (miRNAs) or long non-coding RNAs (lncRNAs) widely regulates the splicing or expression profiles of targeted mRNAs. Recently, we focus on the influence of RNA binding motif protein 4a (RBM4a), a splicing regulator, on the brown adipocyte-related splicing network using transcriptome analyses. Several alternative splicing events are identified throughout the brown adipogenesis or in the RBM4a-/- brown adipose tissues. The impact of RBM4a and its candidates on brown adipogenesis are characterized and published in the BBA-Molecular Cell Research、RNA Biology、Scientific Reports與BBA-Gene Regulatory Mechanism journal. Curcumin and Berberine is documented to enhance the expenditure of triglyceride and repress the white adipogenesis. By using transcriptome analyses, we note the reprogrammed splicing profiles of SRPK1 gene, which is link to the reduced SRPK1 protein levels in CUR/BBR-treated and differentiating brown adipocytes. Moreover, the presence of Curcumin and Berberine mediated the upregulation of miRNA-15, miRNA-21, miRNA-485 and reduction of miR-92a. The putative binding sites of miRNA-485 and miRNA-92a are predicted within the 3' untranslated region of SRPK1 gene and coding region of RBM4a gene in independent miRNA algorithms. Moreover, preliminary results of transcriptome analyses identify the differential expressions of multiple lncRNAs in CUR/BBR-treated cells compared to the proliferating cells. Accordingly, the aims of this project are as follows. (1) The mechanism involves in regulating SRPK1 splicing in differentiating, curcumin- or berberine-treated brown adipocytes is investigated. (2) The impact of SRPK1 on brown adipogenesis by manipulating alternative splicing event and the corresponding mechanism is pursued. To comprehensively understand the influence of CUR and BBR on brown adipocytes, more reprogrammed AS event in CUR- and BBR-treated cells is further identified using transcriptome analyses. (3) The miRNA-mediated mechanism involves in SRPK1 and RBM4a expression is first demonstrated. The similar strategy is applied to establish other miRNA-target network participates in CUR/BBR-induced brown adipogenesis. (4) To investigate the impact and regulatory mechanism of lncRNA-regulated post-transcriptional control on CUR/BBR-mediated brown adipogenesis. Collectively, these results could bring a comprehensive insight into the post-transcriptional network participates in brown adipogenesis. Moreover, the related results could be subjected to develop clinical application of Curcumin and Berberine for combating obesity, metabolic disorder, and related disease.