Review
Transcriptional coregulators in the control of energy homeostasis

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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.

Introduction

Transcriptional regulation is vital for homeostasis and enables the adaptation of physiological processes to external cues [1]. The transcriptional control of metabolism is conserved from simple prokaryotes to complex eukaryotes such as humans. In eukaryotes, nuclear receptors (NRs; see Glossary) and several other transcription factors are key players that integrate signals from dietary, metabolic and endocrine pathways to control target gene expression (2, 3 and Box 1). This enables them to coordinate metabolic processes by adapting tissue responses to various challenges and by tuning interorgan communication through the integration of both endogenous and exogenous signals. NRs themselves confer a first level of specificity to these mechanisms in space and time through their tissue-specific expression patterns, their specific binding to target gene promoters, and through the tuning of their activity via post-translational modifications and ligand binding. Transcription factors, however, do not function alone and require coregulators to modify and epigenetically remodel chromatin structure and to bridge the complexes in which they reside to the basal transcriptional machinery. These coregulators, which can both have positive (coactivator) and negative (corepressor) actions on target gene transcription 4, 5, 6, thus confer a second level of specificity to the transcriptional response (Figure 1). The activity of coregulators is, in turn, regulated through the spatial and temporal control of their expression and activity in response to metabolic cues. Furthermore, transcriptional coregulators constitute a huge reservoir of interacting partners, comprising more than 200 proteins. This diversity allows them to establish specific yet interdependent interaction networks that determine the specificity of the transcriptional complexes.

Metabolic homeostasis requires a tight regulation of the equilibrium between energy intake, storage and expenditure (Figure 1). The mechanisms controlling energy intake involve both the control of nutrient uptake in the gut and the regulation of appetite, which is controlled centrally and involves a hormonal communication between the brain and peripheral tissues such as the gastrointestinal tract and the adipose tissue [7]. Despite recent progress in the identification of peptides controlling appetite, and of their downstream signaling pathways, the potential cross-talk with transcriptional coregulators remains unexplored. By contrast, the implication of coregulators in regulatory nodes controlling energy storage and expenditure has grown exponentially in the past few years. This review therefore focuses on these two aspects of energy homeostasis. Given the potential value of new preventive and therapeutic applications to target metabolic disorders by modulating coregulator activity, we highlight recent work that emphasizes the importance of post-translational modifications to determine coregulator action.

Section snippets

Coregulators and the regulation of energy storage

In higher eukaryotes, energy can be stored as carbohydrates or as lipids. Carbohydrates, which are stored as glycogen in muscle and the liver, can be rapidly mobilized in response to high energy demands, such as those occurring during exercise or fasting. Lipids, stored as triglycerides in the adipose tissue, constitute a long-term energy reservoir. To our knowledge, the implication of NR coregulators in glycogen synthesis and degradation has not been described. Coregulators, however, were

Coregulators and the regulation of energy expenditure

Although the effect of coregulators on energy storage can contribute to whole-body energy homeostasis, abnormalities in energy expenditure are often the major determinants of metabolic disorders. The global impact of coregulators on whole-body energy homeostasis depends on their capacity to modulate the metabolic balance by promoting or inhibiting anabolic and catabolic functions (Figure 2). Whereas WAT is the main organ implicated in the regulation of energy storage by coregulators (see

The future of coregulators

Coregulators are clearly emerging as predominant players in metabolism, which, beyond the control of ‘metabolic’ gene expression by transcription factors, provide a second, more global, level of transcriptional ‘metabolic adaptation’ (Figure 1). An extensive body of work already implicates the PGC-1 coactivators as being central to many metabolic regulatory networks. Furthermore, the implication of other coactivators in energy homeostasis is also becoming more and more evident. Whereas all

Acknowledgements

We thank members of the Auwerx laboratory for stimulating discussions. Work in the authors’ laboratory was supported by grants from CNRS, INSERM, ULP, Hôpital Universitaire de Strasbourg, FRM, AFM, EU and NIH. J.N.F. is supported by a FEBS fellowship.

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