Transcriptional coregulators in the control of energy homeostasis

Metabolic programs controlling energy homeostasis are governed at the transcriptional level by the integrated action of several transcription factors. Among these, nuclear receptors including peroxisome proliferator-activated receptors, estrogen-related receptors or thyroid hormone receptors play prominent roles by adapting gene expression programs to the endocrine and metabolic context that they sense via their ligand-binding domain. Coregulators assist nuclear receptors to positively or negatively influence the transcription of target genes, and thereby comprise an integral part of the transcriptional circuitry. This review focuses on how coregulators, including PGC-1 and p160 coactivators, Sirt-1, RIP140 and NCoR corepressors, control the balance between energy storage and expenditure, with a particular emphasis on how these proteins integrate physiological stimuli in vivo. The general picture that emerges indicates that these coregulators are metabolic switches, which convergently regulate metabolic pathways through their pleiotropic interactions with nuclear receptors and other transcription factors.