Decreased visceral adiposity accounts for leptin effect on hepatic but not peripheral insulin action

Leptin decreases visceral fat (VF) and increases peripheral and hepatic insulin action. Here, we generated similar decreases in VF using leptin (Lep), β₃-adrenoreceptor agonism (β3), or food restriction (FR) and asked whether insulin action would be equally improved. For 8 days before the in vivo study, Sprague-Dawley rats (n = 24) were either fed ad libitum [control (Con)], treated with Lep or β3 (CL-316,243) by implanted osmotic mini-pumps, or treated with FR. Total VF was similarly decreased in the latter three groups (Lep, 3.11 ± 0.96 g; β3, 2.87 ± 0.48 g; and FR, 3.54 ± 0.77 g compared with 6.91 ± 1.41 g in Con; P < 0.001) independent of total fat mass (by ³H₂O) and food intake. Insulin (3 mU · kg^-1 · min^-1) clamp studies were performed to assess hepatic and peripheral insulin sensitivity. Decreased VF resulted in similar and marked improvements in insulin action on glucose production (GP) (Lep, 1.19 ± 0.51; β3, 1.46 ± 0.68; FR, 2.27 ± 0.71 compared with 6.06 ± 0.70 mg · kg^-1 · min^-1 in Con; P < 0.001). By contrast, reduction in VF by β3 and FR failed to reproduce the stimulation of insulin-mediated glucose uptake (~60%), glycogen synthesis (~80%), and glycolysis (~25%) observed with Lep. We conclude that 1) a moderate decrease in VF uniformly leads to a marked increase in hepatic insulin action, but 2) the effects of leptin on peripheral insulin action are not due to the associated changes in VF or β3 activation.