RBM4a-SRSF3-MAP4K4 Splicing Cascade Constitutes a Molecular Mechanism for Regulating Brown Adipogenesis

An increase in mitogen-activated protein kinase kinasekinase 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 adipogenesisremains 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 splicingprofiles of MAP4K4 or SRSF3 were noted as well in brownadipocytes (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 factorfunctioned as a novel regulator toward MAP4K4 splicingduring brown adipogenesis. The presence of alternatively splicedMAP4K4 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 splicingcascade constitutes a novel molecular mechanism in manipulating the development of BAs through related signaling pathways.