We directly examined whether visceral fat (VF) modulates hepatic
insulin action by randomizing moderately obese (body wt approximately 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 x kg(-1) x 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 approximately 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-alpha (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.