[PDF][PDF] The Sam68 STAR RNA-binding protein regulates mTOR alternative splicing during adipogenesis

MÉ Huot, G Vogel, A Zabarauskas, CTA Ngo… - Molecular cell, 2012 - cell.com
MÉ Huot, G Vogel, A Zabarauskas, CTA Ngo, J Coulombe-Huntington, J Majewski
Molecular cell, 2012cell.com
We 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 …
Summary
We 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.
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