RBM4a-SRSF3-MAP4K4 Splicing Cascade Constitutes a Molecular Mechanism for Regulating Brown Adipogenesis
School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan
Ph.D. Program in Medicine Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan
Immunology Research Center, National Health Research Institutes, Zhunan 35053, Taiwan
School of Chinese Medicine, China Medical University, Taichung 40402, Taiwan
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2018, 19(9), 2646; https://doi.org/10.3390/ijms19092646
Received: 7 August 2018 / Revised: 24 August 2018 / Accepted: 4 September 2018 / Published: 6 September 2018
(This article belongs to the Special Issue Nutrition, Brown and White Adipose Tissue)
An increase in mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) reportedly attenuates insulin-mediated signaling which participates in the development of brown adipose tissues (BATs). Nevertheless, the effect of MAP4K4 on brown adipogenesis remains largely uncharacterized. In this study, results of a transcriptome analysis (also referred as RNA-sequencing) showed differential expressions of MAP4K4 or SRSF3 transcripts isolated from distinct stages of embryonic BATs. The discriminative splicing profiles of MAP4K4 or SRSF3 were noted as well in brown adipocytes (BAs) with RNA-binding motif protein 4-knockout (RBM4−/−) compared to the wild-type counterparts. Moreover, the relatively high expressions of authentic SRSF3 transcripts encoding the splicing factor functioned as a novel regulator toward MAP4K4 splicing during brown adipogenesis. The presence of alternatively spliced MAP4K4 variants exerted differential effects on the phosphorylation of c-Jun N-terminal protein kinase (JNK) which was correlated with the differentiation or metabolic signature of BAs. Collectively, the RBM4-SRSF3-MAP4K4 splicing cascade constitutes a novel molecular mechanism in manipulating the development of BAs through related signaling pathways.