Coste, AgnèsLouet, Jean-FrancoisLagouge, MarieLerin, CarlesAntal, Maria CristinaMeziane, HamidSchoonjans, KristinaPuigserver, PereO'Malley, Bert W.Auwerx, Johan2009-04-022009-04-02200810.1073/pnas.0808207105https://infoscience.epfl.ch/handle/20.500.14299/36591WOS:0002609138000701386418957541Transcriptional 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-1alpha. By controlling the expression of the only characterized PGC-1alpha acetyltransferase GCN5, SRC-3 induces PGC-1alpha acetylation and consequently inhibits its activity. Interestingly, SRC-3 expression is induced by caloric excess, resulting in the inhibition of PGC-1alpha activity and energy expenditure, whereas caloric restriction reduces SRC-3 levels leading to enhanced PGC-1alpha activity and energy expenditure. Collectively, these data suggest that SRC-3 is a critical link in a cofactor network that uses PGC-1alpha as an effector to control mitochondrial function and energy homeostasis.text::journal::journal article::research article