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

Agnès Coste, Jean Francois Louet, Marie Lagouge, Carles Lerin, Maria Cristina Antal, Hamid Meziane, Kristina Schoonjans, Pere Puigserver, Bert W. O'Malley, Johan Auwerx

Research output: Contribution to journalArticle

Abstract

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 languageEnglish (US)
Pages (from-to)17187-17192
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number44
DOIs
StatePublished - Nov 4 2008
Externally publishedYes

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Keywords

  • Acetyltransferase
  • Caloric restriction
  • Cofactors
  • Deacetylase
  • SIRT1

ASJC Scopus subject areas

  • General

Cite this

Coste, A., Louet, J. F., Lagouge, M., Lerin, C., Antal, M. C., Meziane, H., Schoonjans, K., Puigserver, P., O'Malley, B. W., & Auwerx, J. (2008). The genetic ablation of SRC-3 protects against obesity and improves insulin sensitivity by reducing the acetylation of PGC-1α. Proceedings of the National Academy of Sciences of the United States of America, 105(44), 17187-17192. https://doi.org/10.1073/pnas.0808207105