Surgical removal of visceral fat reverses hepatic insulin resistance

We directly examined whether visceral fat (VF) modulates hepatic insulin ac tion by randomizing moderately obese (body wt similar to 400 g) Sprague-Daw ley 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 (H2O)-H-3) was not significantly different, The rates of insulin infusion r equired to maintain plasma glucose levels and basal hepatic glucose product ion in the presence of hepatic-pancreatic clamp were markedly increased 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 hig her in the VF+ group (P < 0.001). The heightened hepatic insulin sensitivit y is supported by the decrease in gene expression of both glucose-6-phospha tase and PEPCK and by physiological hyperinsulinemia in VF- but not VF+ rat s. The improvement in hepatic Insulin sensitivity in VF- rats was also supp orted by a similar to 70% decrease in the plasma levels of insulin-like gro wth factor binding protein-1, a marker of insulin's transcription regulatio n in the liver. The removal of PF 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 modul ator of insulin action on hepatic glucose production and gene expression.