The Sam68 STAR RNA-Binding Protein Regulates mTOR Alternative Splicing during Adipogenesis

SummaryWe report that mice ablated for the Sam68 RNA-binding protein exhibit a lean phenotype as a result of increased energy expenditure, decreased commitment to early adipocyte progenitors, and defects in adipogenic differentiation. The Sam68−/− mice were protected from obesity, insulin resistance, and glucose intolerance induced with a high-fat diet. To identify the alternative splice events regulated by Sam68, genome-wide exon usage profiling in white adipose tissue was performed. Adipocytes from Sam68−/− mice retained intron 5 within the mTOR transcript introducing a premature termination codon, leading to an unstable mRNA. Consequently, Sam68-depleted cells had reduced mTOR levels resulting in lower levels of insulin-stimulated S6 and Akt phosphorylation leading to defects in adipogenesis, and this defect was rescued by the exogenous expression of full-length mTOR. Sam68 bound intronic splice elements within mTOR intron 5 required for the usage of the 5′ splice site. We propose that Sam68 regulates alternative splicing during adipogenesis.

Graphical AbstractFigure optionsDownload high-quality image (231 K)Download as PowerPoint slideHighlights
► Sam68−/− mice are lean and protected against dietary-induced obesity
► Sam68−/− mice have adipogenesis defects with fewer pericytes in white adipose tissue
► Sam68 regulates the splicing of the mTOR gene, resulting in reduced mTOR signaling
► The inclusion of mTOR intron 5 leads to an unstable mTOR mRNA isoform of 1 kb