Tirzepatide’s role in targeting adipose tissue macrophages to reduce obesity-related inflammation and improve insulin resistance

•Tirzepatide effectively alleviated visceral adipose inflammation by inhibiting M1-type macrophage infiltration in visceral adipose tissue of obese mice.•Tirzepatide promotes M1-type macrophage apoptosis and reduces inflammatory factor secretion by inhibiting ERK phosphorylation.•Tirzepatide mitigates visceral adipose inflammation, reduces insulin resistance, and improves glucose and lipid metabolism disorders. Obesity and type 2 diabetes mellitus (T2DM) are significant global health challenges, with adipose tissue inflammation being a pivotal contributor to metabolic dysfunction. The involvement of adipose tissue macrophages (ATMs) in obesity-associated inflammation is well recognized, yet the therapeutic strategies specifically targeting ATM-mediated inflammation remain limited. This study aims to explore the effects of tirzepatide, a novel dual GLP-1 and GIP receptor agonist, on ATMs, adipose tissue inflammation, and insulin resistance in the context of obesity. Obese mouse models were established through high-fat diet feeding and subsequently treated with tirzepatide at a dose of 1.2 mg/kg twice weekly for 12 weeks. The study assessed the impact on ATM phenotype, inflammatory markers, and key metabolic indicators. Tirzepatide treatment significantly mitigated the infiltration of pro-inflammatory M1 ATMs within adipose tissue and concurrently reduced levels of inflammatory cytokines, thereby enhancing insulin sensitivity. Tirzepatide demonstrated therapeutic efficacy through its modulation of the ERK signaling pathway and promotion of M1-type macrophage apoptosis. Tirzepatide’s potential as a therapeutic strategy for addressing metabolic diseases associated with obesity and T2DM by targeting ATM activity and mitigating obesity-associated inflammation.