- In established obesity inflammation and macrophage recruitment likely contribute to the development of insulin resistance. In the present study, we set to explore whether adipose tissue infiltration by neutrophils that occurs early (3 days) after initiating high-fat diet (3dHFD) could contribute to the early occurrence of hepatic insulin resistance, and to determine the role of cytosolic phospholipaseA2α (cPLA2α) in this process. 3dHFD caused a significant upregulation of cPLA2α in peri-epididymal fat and in the liver. A specific antisense oligonucleotide (AS) effectively prevented cPLA2α induction, neutrophil infiltration into adipose tissue (likely involving MIP-2), and protected against 3dHFD-induced impairment in hepatic insulin signaling and glucose over-production from pyruvate. To sort out the role of adipose neutrophil infiltration independent of cPLA2α induction in the liver, mice were injected intraperitoneally with anti-ICAM-1 antibodies. This effectively prevented neutrophil infiltration without affecting cPLA2α or MIP-2, but like AS, prevented impairment in hepatic insulin signaling, the enhanced glucose-to-pyruvate flux, and the impaired insulin-mediated suppression of hepatic glucose production (assessed by clamp), which were induced by 3dHFD. Adipose tissue secretion of TNFα was increased by 3dHFD, but not if mice were treated with AS or ICAM-1 antibodies. Moreover, systemic TNFα neutralization prevented 3dHFD-induced hepatic insulin resistance, suggesting its mediatory role. We propose that an acute, cPLA2α-dependent, neutrophil-dominated inflammatory response of adipose tissue contributes to hepatic insulin resistance and glucose overproduction in the early adaptation to high-fat feeding.