Peroxisome Proliferator-Activated Receptor Signaling in Metabolic Disorders

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptor transcription factors that function as lipid and energy sensors to regulate metabolic homeostasis. Three isoforms—PPARα, PPARβ/δ and PPARγ—heterodimerise with retinoid X receptors and bind peroxisome proliferator response elements to control genes involved in fatty acid oxidation, adipogenesis, glucose utilisation and anti-inflammatory responses. Aberrant PPAR signalling has been implicated in the pathogenesis of type 2 diabetes, dyslipidaemia, non-alcoholic fatty liver disease and obesity. Pharmacological ligands such as fibrates and thiazolidinediones have demonstrated efficacy in normalising lipid profiles and improving insulin sensitivity, yet their clinical utility is tempered by adverse effects that underscore the need for more selective modulators. Current research focuses on the dynamic conformational states of the PPAR ligand-binding domain, coactivator recruitment profiles and cross-talk with inflammatory and oxidative-stress pathways, offering new avenues for safer and tissue-specific interventions in metabolic disorders.

Research from Nature Portfolio

Recent studies have delineated the conformational ensemble of PPARγ in response to diverse ligands spanning inverse agonists to full agonists. High-resolution crystal structures captured previously elusive repressive conformations stabilised by inverse agonists, while NMR spectroscopy revealed that subtle chemical modifications shift the receptor between transcriptionally active and repressive states. These findings establish a molecular framework for designing ligands that finely tune PPARγ activity, potentially enabling more precise control of adipocyte differentiation, lipid handling and insulin sensitivity with reduced off-target effects.

Peroxisome Proliferator-Activated Receptor Signaling in Metabolic Disorders publication trend

The graph below shows the total number of articles in peroxisome proliferator-activated receptor signaling in metabolic disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Peroxisome proliferator-activated receptor (PPAR): A subfamily of nuclear receptors (α, β/δ, γ) that regulate genes involved in lipid metabolism, glucose homeostasis and inflammation.

Agonist/antagonist/inverse agonist: Ligands that respectively activate, block or repress the basal activity of nuclear receptors, shaping transcriptional outcomes.

Selective PPAR modulator (SPPARM): A ligand that confers isoform- or tissue-selective modulation of PPAR activity to maximise therapeutic benefit and minimise side effects.

Conformational ensemble: The dynamic repertoire of receptor shapes populated in the absence or presence of ligands, affecting coactivator or corepressor recruitment.

Coactivator: A protein that associates with ligand-bound nuclear receptors to facilitate transcriptional activation by modifying chromatin or recruiting the transcriptional machinery.

References

1. Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family in physiological and pathophysiological process and diseases. Signal Transduction and Targeted Therapy (2024).
2. Ligand efficacy shifts a nuclear receptor conformational ensemble between transcriptionally active and repressive states. Nature Communications (2025).
3. Identification of an alternative ligand‐binding pocket in peroxisome proliferator‐activated receptor gamma and its correlated selective agonist for promoting beige adipocyte differentiation. MedComm (2024).
4. FGF2 Mediated USP42‐PPARγ Axis Activation Ameliorates Liver Oxidative Damage and Promotes Regeneration. Advanced Science (2025).