Area de Bioquímica, Facultad de Químicas, Regional Centre for Biomedical Research, Universidad de Castilla-La Mancha, 13071 Ciudad Real, Spain.
Endocrinology. 2011 Apr;152(4):1366-77. doi: 10.1210/en.2010-0858. Epub 2011 Feb 1.
Leptin enhances the glucose utilization in most insulin target tissues and paradoxically decreases it in white adipose tissue (WAT), but knowledge of the mechanisms underlying the inhibitory effect of central leptin on the insulin-dependent glucose uptake in WAT is limited. After 7 d intracerebroventricular leptin treatment (0.2 μg/d) of rats, the overall insulin sensitivity and the responsiveness of WAT after acute in vivo insulin administration were analyzed. We also performed unilateral WAT denervation to clarify the role of the autonomic nervous system in leptin effects on the insulin-stimulated [(3)H]-2-deoxyglucose transport in WAT. Central leptin improved the overall insulin sensitivity but decreased the in vivo insulin action in WAT, including insulin receptor autophosphorylation, insulin receptor substrate-1 tyrosine-phosphorylation, and Akt activation. In this tissue, insulin receptor substrate-1 and glucose transporter 4 mRNA and protein levels were down-regulated after central leptin treatment. Additionally, a remarkable up-regulation of resistin, together with an augmented expression of suppressor of cytokine signaling 3 in WAT, was also observed in leptin-treated rats. As a result, the insulin-stimulated glucose transporter 4 insertion at the plasma membrane and the glucose uptake in WAT were impaired in leptin-treated rats. Finally, denervation of WAT abolished the inhibitory effect of central leptin on glucose transport and decreased suppressor of cytokine signaling 3 and resistin levels in this tissue, suggesting that resistin, in an autocrine/paracrine manner, might be a mediator of central leptin antagonism of insulin action in WAT. We conclude that central leptin, inhibiting the insulin-stimulated glucose uptake in WAT, may regulate glucose availability for triacylglyceride formation and accumulation in this tissue, thereby contributing to the control of adiposity.
瘦素增强了大多数胰岛素靶组织中的葡萄糖利用，而在白色脂肪组织（WAT）中却降低了其葡萄糖利用，但中枢瘦素对 WAT 中胰岛素依赖性葡萄糖摄取的抑制作用的机制知之甚少。在对大鼠进行 7 天的侧脑室瘦素治疗（0.2 μg/d）后，分析了整体胰岛素敏感性和急性体内胰岛素给药后 WAT 的反应性。我们还进行了单侧 WAT 去神经支配，以阐明自主神经系统在瘦素对 WAT 中胰岛素刺激的[3H]-2-脱氧葡萄糖转运的影响中的作用。中枢瘦素改善了整体胰岛素敏感性，但降低了 WAT 中的体内胰岛素作用，包括胰岛素受体自身磷酸化、胰岛素受体底物-1 酪氨酸磷酸化和 Akt 激活。在该组织中，胰岛素受体底物-1 和葡萄糖转运蛋白 4 的 mRNA 和蛋白水平在中枢瘦素处理后下调。此外，在瘦素处理的大鼠中还观察到抵抗素的显著上调，以及细胞因子信号抑制物 3 的表达增加。因此，胰岛素刺激的葡萄糖转运蛋白 4 在质膜中的插入和 WAT 中的葡萄糖摄取受损。最后，WAT 的去神经支配消除了中枢瘦素对葡萄糖转运的抑制作用，并降低了该组织中的细胞因子信号抑制物 3 和抵抗素水平，表明抵抗素以自分泌/旁分泌方式可能是中枢瘦素拮抗胰岛素在 WAT 中作用的介质。我们得出结论，中枢瘦素抑制 WAT 中胰岛素刺激的葡萄糖摄取，可能调节该组织中三酰甘油形成和积累的葡萄糖可用性，从而有助于控制肥胖。
