Transcriptional Regulation of Nuclear Receptors in Metabolic Disorders

Nuclear receptors form a superfamily of ligand‐dependent transcription factors that orchestrate the expression of genes governing lipid, carbohydrate and energy metabolism. Through direct binding to DNA response elements, these receptors recruit a dynamic repertoire of coregulators and chromatin remodellers to fine‐tune programmes of metabolic gene expression. Orphan nuclear receptors, despite lacking defined endogenous ligands, are equally central to metabolic homeostasis, acting via ligand‐independent mechanisms and interactions with transcriptional coactivators or corepressors. Dysregulation of nuclear receptor signalling contributes to the pathogenesis of obesity, insulin resistance, non-alcoholic fatty liver disease and type 2 diabetes. Advances in genome-wide mapping of receptor binding, together with an expanded understanding of post-translational modifications and cofactor networks, have opened new avenues for therapeutic intervention. Small-molecule modulators, inverse agonists and receptor-selective ligands are now under preclinical evaluation, highlighting the promise of targeting transcriptional control pathways to restore metabolic balance.

Research from Nature Portfolio

No recent Nature Portfolio content available.

Transcriptional Regulation of Nuclear Receptors in Metabolic Disorders publication trend

The graph below shows the total number of articles in transcriptional regulation of nuclear receptors in metabolic disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Nuclear receptor: A class of transcription factors that bind small molecules and regulate gene expression by recognising specific DNA sequences.

Orphan nuclear receptor: A receptor within the nuclear superfamily for which a physiological ligand has not been identified, yet which can modulate transcription via ligand-independent mechanisms.

Transcriptional coactivator: A protein that associates with DNA-bound transcription factors to enhance assembly of the transcriptional machinery without directly binding DNA.

Chromatin immunoprecipitation (ChIP): A technique to capture and identify DNA regions bound by specific proteins, often coupled with sequencing to map binding sites genome-wide.

Response element: A defined DNA sequence in gene promoters or enhancers that is specifically recognised and bound by a nuclear receptor to regulate transcription.

References

1. ERRα as a Bridge Between Transcription and Function: Role in Liver Metabolism and Disease. Frontiers in Endocrinology (2019).
2. Peroxisome Proliferator-activated Receptor Coactivator-1α (PGC-1α) Coactivates the Cardiac-enriched Nuclear Receptors Estrogen-related Receptor-α and -γ IDENTIFICATION OF NOVEL LEUCINE-RICH INTERACTION MOTIF WITHIN PGC-1α*. Journal of Biological Chemistry (2002).
3. The Transcriptional Coactivator PGC-1 Regulates the Expression and Activity of the Orphan Nuclear Receptor Estrogen-Related Receptor α (ERRα)*. Journal of Biological Chemistry (2003).
4. Orphan Nuclear Receptor Estrogen-Related Receptor γ (ERRγ) Is Key Regulator of Hepatic Gluconeogenesis*. Journal of Biological Chemistry (2012).