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Transcriptional control of energy metabolism by nuclear receptors

Abstract

Transcriptional regulation of catabolic pathways is a central mechanism by which cells respond to physiological cues to generate the energy required for anabolic pathways, transport of molecules and mechanical work. Nuclear receptors are members of a superfamily of transcription factors that transduce hormonal, nutrient, metabolite and redox signals into specific metabolic gene programmes, and thus hold a major status as regulators of cellular energy generation. Nuclear receptors also regulate the expression of genes involved in cellular processes that are implicated in energy production, including mitochondrial biogenesis and autophagy. Recent advances in genome-wide approaches have considerably expanded the repertoire of both nuclear receptors and metabolic genes under their direct transcriptional control. To fine-tune the expression of their target genes, nuclear receptors must act cooperatively with other transcription factors and coregulator proteins, integrate signals from key metabolic sensory systems such as the AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) complexes and synchronize their activities with the biological clock. Therefore, nuclear receptors must function as more than molecular switches for small lipophilic ligands — as initially ascribed — but rather must be capable of orchestrating a large ensemble of input signals. Therefore, a primary role for several nuclear receptors is to serve as the focal point of transcriptional hubs in energy metabolism: their molecular task is to receive and transduce multiple systemic and intracellular metabolic signals to maintain energy homeostasis from individual cells to the whole organism.

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Fig. 1: The nuclear receptor superfamily.
Fig. 2: Basics of nuclear receptor action.
Fig. 3: Regulatory metabolic crosstalk.
Fig. 4: Cellular energy metabolic pathways transcriptionally controlled by nuclear receptors.
Fig. 5: Relative contribution of nuclear receptors to the transcriptional regulation of metabolic genes.
Fig. 6: Nuclear receptor-dependent metabolic regulatory hubs.

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The authors contributed equally to all aspects of the article.

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Correspondence to Vincent Giguère.

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Glossary

Ketone bodies

Small, water-soluble circulating lipids produced by the adult liver that have an important role as an energy source during starvation, especially for the brain.

Catabolism

A series of chemical reactions involved in the degradation of complex macromolecules resulting in the production of energy and small molecules. Catabolic reactions are opposed by anabolic reactions, which consume energy, leading to the synthesis of complex macromolecules from small molecules.

Redox

Abbreviation for ‘reduction–oxidation’. Refers to a chemical reaction in which the oxidation states of atoms are changed. Oxidation is an increase in oxidation state, and reduction is a decrease in oxidation state. Redox homeostasis is the regulation of reactive oxygen species formation and removal inside the cell.

Autophagy

A lysosome-dependent catabolic process whereby cytoplasmic components are degraded and recycled. Autophagy plays an essential role in maintaining cellular energy homeostasis in response to intracellular stress.

DNase I hypersensitive site sequencing

A molecular biology technique used to identify the location of regulatory regions, based on the genome-wide sequencing of regions sensitive to cleavage by DNase I.

Assay for transposase-accessible chromatin using sequencing

A molecular biology technique used to assess genome-wide chromatin accessibility.

Pioneer factors

A class of transcription factors that can associate with compacted chromatin to facilitate the binding of additional transcription factors.

Maturity-onset diabetes of the young, type 1

A rare hereditary form of diabetes caused by a loss-of-function mutation in the HNF4A gene that usually develops in adolescence or early adulthood. It causes high blood glucose levels from reduced production of insulin.

Mediator complex

A multiprotein complex that mediates the interaction between transcription factors, coregulators and the general transcription machinery.

Chromatin immunoprecipitation followed by deep sequencing

(ChIP–seq). Molecular biology technique used to globally identify the binding sites of DNA-associated proteins in a genome.

High-throughput chromosome conformation capture

(Hi-C). A chromosome conformation capture technique used to analyse the spatial organization of chromatin in a cell. Hi-C quantifies the number of interactions between genomic loci that are adjacent in three-dimensional space but separated by lengthy DNA segments in the linear genome.

Global run-on followed by sequencing

A molecular biology technique used to identify the genes that are being actively transcribed. It provides a detailed catalogue of genes engaged in transcription with quantitative levels of expression.

Superenhancers

A group of enhancers located close to each other (less than 12 kb) in the genome and functionally linked together by the mediator complex.

Sirtuin

Evolutionarily conserved family of epigenetic regulators that modulate the activity of their targets by removing covalently attached acetyl groups. They are metabolic sensors sensitive to NAD+ levels that maintain physiological homeostasis.

General control non-depressible 5

(GCN5). Catalytic subunit of several histone acetyltransferase (HAT) complexes reported to play a range of different functions associated with transcription.

One-carbon metabolism

A group of reactions with a set of enzymes that have in common the transfer of one-carbon groups and that play a role in multiple physiological processes, such as biosynthesis, amino acid homeostasis or epigenetic maintenance.

Brown fat

A type of fat tissue very rich in mitochondria that plays a central role in regulating whole-body energy homeostasis and temperature by its capacity to dissipate macronutrient energy as heat.

Regulon

Group of several genes that are activated or inactivated in response to the same signal by the same regulatory protein.

Metabolic flexibility

The capacity to alter metabolism in response to exercise or available fuel. An organism displays metabolic flexibility if it is capable of metabolizing either carbohydrate or fat efficiently, depending on the availability of those fuels. Metabolic inflexibility is the inability to generate enough energy in response to physiological demands.

Slow twitch muscle type

One of the two main types of muscle fibres. This type contains more mitochondria and depends on aerobic respiration. Their role is sustained, smaller movements and postural control.

Reactive oxygen species

(ROS). Reactive molecules and free radicals or non-radicals derived from molecular oxygen.

Free radical

A chemical species unstable with unpaired electrons.

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Scholtes, C., Giguère, V. Transcriptional control of energy metabolism by nuclear receptors. Nat Rev Mol Cell Biol (2022). https://doi.org/10.1038/s41580-022-00486-7

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