PPARagonists

PPARagonists, often referred to as PPAR agonists, are ligands that activate peroxisome proliferator-activated receptors (PPARs), a family of nuclear receptors that regulate gene expression in response to lipid signals and other metabolites. PPARs function as transcription factors and control metabolic processes including lipid oxidation, lipoprotein metabolism, glucose homeostasis, adipogenesis, and inflammatory responses. There are three main isotypes: PPAR-alpha, PPAR-gamma, and PPAR-delta (beta/delta). When a suitable ligand binds, the receptor forms a heterodimer with retinoid X receptor (RXR) and binds to PPAR response elements in DNA to modulate target gene transcription.

Endogenous ligands such as long-chain fatty acids and eicosanoids activate PPARs, linking dietary and metabolic states to gene expression. PPAR-alpha is enriched in liver, muscle, and brown adipose tissue and promotes fatty acid oxidation. PPAR-gamma is abundant in adipose tissue and regulates adipogenesis and insulin sensitivity. PPAR-delta is widely expressed and influences lipid metabolism and energy expenditure.

Clinically used PPAR agonists include fibrates (PPAR-alpha agonists) such as fenofibrate and gemfibrozil, which lower triglycerides and raise HDL cholesterol. Thiazolidinediones (PPAR-gamma agonists) such as pioglitazone and rosiglitazone improve insulin sensitivity in type 2 diabetes but carry risks including weight gain, edema, and cardiovascular events. Dual or pan-PPAR agonists aim to activate more than one PPAR isotype to address multiple metabolic targets; several compounds (e.g., muraglitazar, tesaglitazar) were not approved due to safety concerns. PPAR-delta agonists like GW501516 showed metabolic promise but raised cancer risk concerns and were not pursued clinically.

Overall, PPAR agonists remain important tools in metabolic disease management, with ongoing research into selective and tissue-specific modulators to improve efficacy and safety.