Surgical removal of visceral fat reverses hepatic insulin resistance

We directly examined whether visceral fat (VF) modulates hepatic insulin action by randomizing moderately obese (body wt ~400 g) Sprague-Dawley rats to either surgical removal of epididymal and perinephric fat pads (VF^-; n = 9) or a sham operation (VF⁺; n = 11). Three weeks later, total VF was fourfold increased (8.5 ± 1.2 vs. 2.1 ± 0.3 g, P < 0.001) in the VF⁺ compared with the VF^- group, but whole-body fat mass (determined using ³H₂O) was not significantly different. The rates of insulin infusion required to maintain plasma glucose levels and basal hepatic glucose production in the presence of hepatic-pancreatic clamp were markedly decreased in VF^- compared with VF⁺ rats (0.57 ± 0.02 vs. 1.22 ± 0.19 mU · kg^-1 · min^-1, P < 0.001). Similarly, plasma insulin levels were more than twofold higher in the VF⁺ group (P < 0.001). The heightened hepatic insulin sensitivity is supported by the decrease in gene expression of both glucose-6-phosphatase and PEPCK and by physiological hyperinsulinemia in VF^- but not VF⁺ rats. The improvement in hepatic insulin sensitivity in VF^- rats was also supported by a ~70% decrease in the plasma levels of insulin- like growth factor binding protein-1, a marker of insulin's transcription regulation in the liver. The removal of VF pads also resulted in marked decreases in the gene expression of tumor necrosis factor-α (by 72%) and leptin (by 60%) in subcutaneous fat. We conclude that visceral fat is a potent modulator of insulin action on hepatic glucose production and gene expression.