Abstract: Objective To determine the importance of gastric inhibitory peptide receptor (GIPR) signaling for insulin resistance and hepatic steatosis in the adipose tissue of mice. Methods Four-week-old adipocyte-specific GIPR knockout (GIPRadipo- / - ) and wild-type (WT) mice were fed a control (CD) or high-fat (HFD) diet for 15 weeks ( n= 8 per group). Changes in body mass were recorded, and the circulating glucose, insulin, and total GIP concentrations were measured after 5, 8, 10, 12 and 15 weeks of feeding. Quantitative PCR was used to measure the changes in the expression of genes involved in inflammation and GIPR signaling in adipose tissue; the volume, mass, and fat content of the liver were quantitatively assessed using ultrasonography; and insulin-stimulated AKT phosphorylation in adipose tissue, liver, and skeletal muscle was evaluated using western blot analysis. Results During HFD-feeding, the body mass of the GIPRadipo- / - mice was significantly lower than that of WT mice, and they also demonstrated lower insulin resistance, liver mass, and hepatic steatosis. In addition, the plasma interleukin 6 (IL-6) concentration was lower in the GIPRadipo- / - mice than in the HFD-fed WT mice. Conclusions GIPR signaling in adipose tissue plays a role in HFD-induced insulin resistance and hepatic steatosis in vivo, and this may be mediated through IL-6.