The genetic ablation of SRC-3 protects against obesity and improves insulin sensitivity by reducing the acetylation of PGC-1a

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 105; no. 44; pp. 17187 - 17192
• Main Authors: Coste, Agnes, Louet, Jean-Francois, Lagouge, Marie, Lerin, Carles, Antal, Maria Cristina, Meziane, Hamid, Schoonjans, Kristina, Puigserver, Pere, O'Malley, Bert W, Auwerx, Johan
• Format: Journal Article
• Language: English
• Published: 04.11.2008
• Subjects: Acetylation; Acetyltransferase; Animal subjects; Cofactors; Coordination; Data processing; Dietary restrictions; Diseases; Energy balance; Energy cost; Energy expenditure; Genetics; Hormones; Inhibition; Insulin; Metabolic disorders; Mitochondria; Obesity; PGC-1 protein; Transcription factors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0808207105

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 super(-/-) mice is caused by an increase in mitochondrial function and in energy expenditure as a consequence of activation of PGC-1a. By controlling the expression of the only characterized PGC-1a acetyltransferase GCN5, SRC-3 induces PGC- 1a acetylation and consequently inhibits its activity. Interestingly, SRC-3 expression is induced by caloric excess, resulting in the inhibition of PGC-1a activity and energy expenditure, whereas caloric restriction reduces SRC-3 levels leading to enhanced PGC-1a activity and energy expenditure. Collectively, these data suggest that SRC-3 is a critical link in a cofactor network that uses PGC-1a as an effector to control mitochondrial function and energy homeostasis.