Pioglitazone-Mediated Reduction of Ectopic Fat in Metabolic Dysfunction-Associated Steatotic Liver Disease

Ectopic fat accumulation is a significant metabolic disorder that contributes to insulin resistance, inflammation, and organ dysfunction.Pioglitazone, a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, improves insulin sensitivity and promotes the redistribution of ectopic fat from visceral and non-adipose tissues to subcutaneous adipose tissue.Pioglitazone has been shown to reduce ectopic fat, improve liver histology in metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH), and improve glucose and lipid metabolism.Its effects on hepatic, visceral, pancreatic, intramyocellular, and cardiac fat suggest potential benefits across multiple metabolic conditions.Combination therapy with sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), or other metabolic agents may provide complementary benefits while mitigating pioglitazone-associated weight gain.However, concerns regarding fluid retention, weight gain, and other adverse effects require careful patient selection and monitoring.This narrative review examines the mechanisms by which pioglitazone influences ectopic fat distribution, summarizes evidence across different organ-specific fat depots, and discusses its potential role in combination therapeutic strategies.Further research is needed to clarify its long-term effects on organspecific fat depots and clinical outcomes and to identify patients most likely to benefit from therapy.