PPARG

PPARG, or peroxisome proliferator-activated receptor gamma, is a nuclear receptor transcription factor encoded by the PPARG gene in humans. It functions as a ligand-activated transcription factor that forms a heterodimer with retinoid X receptor (RXR) and binds to peroxisome proliferator response elements in target gene promoters to regulate adipogenesis, lipid metabolism, and insulin sensitivity. Natural ligands include fatty acids and eicosanoids; pharmacologic agonists include thiazolidinediones such as rosiglitazone and pioglitazone.

PPARG is highly expressed in adipose tissue and to lesser extents in the colon, immune cells, and other tissues. It is essential for adipocyte differentiation; activation promotes expression of adipocyte markers and enhances adiponectin production, improving systemic insulin sensitivity. In immune cells, PPARG modulates inflammatory responses, often exerting anti-inflammatory effects.

Mechanistically, ligand binding induces conformational changes that recruit coactivators (e.g., PGC-1alpha, CBP/p300) and release corepressors, leading to transcription of metabolic genes. Post-translational modifications, such as phosphorylation at serine 273 by CDK5, can uncouple insulin-sensitizing gene programs, a modification that TZDs counteract.

Genetic variation in PPARG influences metabolic disease risk. The Pro12Ala (rs1801282) variant is associated in some populations with altered risk of type 2 diabetes and obesity. Mouse models show that adipose-specific PPARG disruption causes lipodystrophy and insulin resistance, while global knockout is embryonically or perinatally lethal, highlighting tissue-specific roles.

PPARG has two major protein isoforms, PPARG1 and PPARG2, which differ in their N-termini and activity. The gene is located on chromosome 3p25.2. Clinically, PPARG is a validated therapeutic target for type 2 diabetes, though TZD use is limited by adverse effects such as weight gain, fluid retention, and potential cardiovascular risks.