Persistent Adipose Inflammation Despite Metabolic Recovery Reveals Tissue-Specific Immunomodulation by Tirzepatide

Background: Obesity is characterized by chronic inflammation and fibrosis of adipose tissue; however, the extent to which these pathological features persist during pharmacologically induced weight loss remains poorly understood. This study investigated the effects of tirzepatide, a dual agonist of the glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptors, on adipose tissue inflammation and fibrosis in obese mice. Methods: Diet-induced obesity was treated with tirzepatide or vehicle for 25 days. Metabolic parameters, tissue inflammation, fibrosis, and macrophage activation were assessed using histology, flow cytometry, gene expression analyses, and immunoblotting. In vitro experiments were conducted to compare the effects of tirzepatide on classically activated and metabolically activated macrophages. Results: Tirzepatide significantly reduced body weight and adiposity, increased energy expenditure, and upregulated thermogenic and mitochondrial proteins in brown adipose tissue. Hyperglycemia and glucose intolerance were normalized. However, adipose tissue inflammation and fibrosis persisted despite weight loss, as evidenced by sustained immune cell infiltration, collagen deposition, and activation of Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) signaling. In contrast, hepatic inflammation and fibrosis were substantially improved. Mechanistically, tirzepatide suppressed inflammatory gene expression in classically activated macrophages but not in metabolically activated macrophages, suggesting that the local metabolic context determines tissue responsiveness to its anti-inflammatory actions. Conclusion: Tirzepatide exerts distinct tissue-specific effects on inflammation and fibrosis during weight loss, ameliorating hepatic pathology while sparing adipose tissue inflammation. These findings identify metabolically activated macrophages as potential determinants of tissue-specific inflammatory persistence and underscore the need for therapeutic strategies that target macrophage activation and fibrotic remodeling to achieve durable metabolic benefits during pharmacological weight loss.