Transcriptional control of metabolic circuits requires coordination between specific transcription factors and coregulators and is often deregulated in metabolic diseases. We characterized here the mechanisms through which the coactivator SRC-3 controls energy homeostasis. SRC-3 knock-out mice present a more favorable metabolic profile relative to their wild-type littermates. This metabolic improvement in SRC-3-/- mice is caused by an increase in mitochondrial function and in energy expenditure as a consequence of activation of PGC-1α. By controlling the expression of the only characterized PGC-1α acetyltransferase GCN5, SRC-3 induces PGC-1α acetylation and consequently inhibits its activity. Interestingly, SRC-3 expression is induced by caloric excess, resulting in the inhibition of PGC-1α activity and energy expenditure, whereas caloric restriction reduces SRC-3 levels leading to enhanced PGC-1α activity and energy expenditure. Collectively, these data suggest that SRC-3 is a critical link in a cofactor network that uses PGC-1α as an effector to control mitochondrial function and energy homeostasis.
|Original language||English (US)|
|Number of pages||6|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|State||Published - Nov 4 2008|
- Caloric restriction
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