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Peroxisome proliferator-activated receptor gamma (PPARγ) is closely linked to energy homeostasis regulation, playing important role in adipogenesis, lipid and carbohydrates metabolism, insulin sensitivity, cell proliferation, and inflammatory processes. This nuclear receptor (NR) acts as a metabolic sensor of dietary lipids and is a crucial metabolism modulator (1, 2), regulating diabetes through cytokines and hormones, such as TNFαand leptin genes (2–4). Like other NR superfamily members, PPARγ is activated by natural ligands, such as fatty acids and their metabolites, and by synthetic ligands such as the insulin sensitizers Thiazolidinediones (TZDs), as Rosiglitazone and Pioglitazone, drugs commonly used in type 2 diabetes treatment.

The canonical transcriptional activity of PPARγ occurs through its interaction with several cofactors, which activate or suppress gene transcription. In the absence of ligands, the inactive conformation of helix 12 (H12) of PPARγ ligand binding domain (LBD), favors the binding of corepressor proteins, such as silencing mediator of retinoid and thyroid hormone receptor (SMRT) and the nuclear receptor corepressor 1 (NCoR). These proteins form a corepressor complex with histone deacetylases (HDAC) repressing target gene transcription (5). In the presence of ligands, the receptor undergoes a conformational change, that reallocates H12, forming a charge clamp between H3 and H12 (6). This conformation leads to corepressors dissociation and coactivators recruitment, forming a coactivator complex by the recruitment of other proteins, as well as histone acetyltransferases (HAT) and other general transcription …