German Jonathan, Kim Francis, Schwartz Gary J, Havel Peter J, Rhodes Christopher J, Schwartz Michael W, Morton Gregory J
Department of Medicine, University of Washington at South Lake Union, 815 Mercer Street, Box 358055, Seattle, Washington 98195.
Endocrinology. 2009 Oct;150(10):4502-11. doi: 10.1210/en.2009-0445. Epub 2009 Jul 2.
Recent evidence suggests that hormones such as insulin and leptin act in the hypothalamus to regulate energy balance and glucose metabolism. Here we show that in leptin receptor-deficient Koletsky (fa(k)/fa(k)) rats, adenovirally induced expression of leptin receptors in the area of the hypothalamic arcuate nucleus improved peripheral insulin sensitivity via enhanced suppression of hepatic glucose production, with no change of insulin-stimulated glucose uptake or disposal. This effect was associated with increased insulin signal transduction via phosphatidylinositol-3-OH kinase (as measured by pY-insulin receptor substrate-1 and pS-PKB/Akt) in liver, but not skeletal muscle, and with reduced hepatic expression of the gluconeogenic genes, glucose-6-phosphatase and phosphoenolpyruvate kinase. Moreover, the beneficial effects of hypothalamic leptin signaling on hepatic insulin sensitivity were blocked by selective hepatic vagotomy. We conclude that hypothalamic leptin action increases peripheral insulin sensitivity primarily via effects on the liver and that the mechanism underlying this effect is dependent on the hepatic branch of the vagus nerve.
近期证据表明，胰岛素和瘦素等激素在下丘脑中发挥作用，以调节能量平衡和葡萄糖代谢。在此我们表明，在瘦素受体缺陷的科列茨基（fa(k)/fa(k)）大鼠中，腺病毒介导的下丘脑弓状核区域瘦素受体表达通过增强对肝葡萄糖生成的抑制作用改善了外周胰岛素敏感性，而胰岛素刺激的葡萄糖摄取或处置未发生变化。这种效应与肝脏而非骨骼肌中通过磷脂酰肌醇-3-OH激酶的胰岛素信号转导增加（通过pY-胰岛素受体底物-1和pS-PKB/Akt测量）以及糖异生基因葡萄糖-6-磷酸酶和磷酸烯醇丙酮酸激酶的肝脏表达降低有关。此外，选择性肝迷走神经切断术阻断了下丘脑瘦素信号对肝脏胰岛素敏感性的有益作用。我们得出结论，下丘脑瘦素作用主要通过对肝脏的影响增加外周胰岛素敏感性，并且这种效应的潜在机制依赖于迷走神经的肝分支。
