Thromboxane A₂-TP axis promotes adipose tissue macrophages M1 polarization leading to insulin resistance in obesity

Aberrant arachidonic acid metabolism has been implicated in multiple pathophysiological conditions, and the downstream prostanoids levels are associated with adipocyte dysfunction in obesity. However, the role of thromboxane A₂ (TXA₂) in obesity remains unclear. We observed that TXA₂, through its receptor TP, is a candidate mediator in obesity and metabolic disorders. Obese mice with upregulated TXA₂ biosynthesis (TBXAS1) and TXA₂ receptor (TP) expression in caused insulin resistance and macrophage M1 polarization in white adipose tissue (WAT), which can be prevented by treatment with aspirin. Mechanistically, the activation of TXA₂-TP signaling axis leads to accumulation of protein kinase Cɛ (PKCɛ), thereby enhancing free fat acid (FFA) induced Toll-like receptor4 (TLR4) proinflammatory macrophage activation and the tumor necrosis factor-a (TNF-a) production in adipose tissues. Importantly, TP knockout mice reduced the accumulation of proinflammatory macrophages and adipocyte hypertrophy in WAT. Thus, our findings demonstrate that TXA₂-TP axis plays a crucial role in obesity-induced adipose macrophage dysfunction, and rational targeting TXA₂ pathway may improve obesity and its associated metabolic disorders in future. In this work, we establish previously unknown role of TXA₂-TP axis in WAT. These findings might provide new insight into the molecular pathogenesis of insulin resistance, and indicate rational targeting TXA₂ pathway to improve obesity and its associated metabolic disorders in future.