Department of Medicine, Diabetes Research Center, Albert EinsteinCollege of Medicine, Bronx, New York, USA.
Diabetes. 2011 Nov;60(11):2691-700. doi: 10.2337/db10-0987. Epub 2011 Sep 6.
Sirtuin 1 (SIRT1) and its activator resveratrol are emerging as major regulators of metabolic processes. We investigate the site of resveratrol action on glucose metabolism and the contribution of SIRT1 to these effects. Because the arcuate nucleus in the mediobasal hypothalamus (MBH) plays a pivotal role in integrating peripheral metabolic responses to nutrients and hormones, we examined whether the actions of resveratrol are mediated at the MBH.
Sprague Dawley (SD) male rats received acute central (MBH) or systemic injections of vehicle, resveratrol, or SIRT1 inhibitor during basal pancreatic insulin clamp studies. To delineate the pathway(s) by which MBH resveratrol modulates hepatic glucose production, we silenced hypothalamic SIRT1 expression using a short hairpin RNA (shRNA) inhibited the hypothalamic ATP-sensitive potassium (K(ATP)) channel with glibenclamide, or selectively transected the hepatic branch of the vagus nerve while infusing resveratrol centrally.
Our studies show that marked improvement in insulin sensitivity can be elicited by acute administration of resveratrol to the MBH or during acute systemic administration. Selective inhibition of hypothalamic SIRT1 using a cell-permeable SIRT1 inhibitor or SIRT1-shRNA negated the effect of central and peripheral resveratrol on glucose production. Blockade of the K(ATP) channel and hepatic vagotomy significantly attenuated the effect of central resveratrol on hepatic glucose production. In addition, we found no evidence for hypothalamic AMPK activation after MBH resveratrol administration.
Taken together, these studies demonstrate that resveratrol improves glucose homeostasis mainly through a central SIRT1-dependent pathway and that the MBH is a major site of resveratrol action.
Sirtuin 1（SIRT1）及其激活剂白藜芦醇作为代谢过程的主要调节剂而备受关注。我们研究了白藜芦醇对葡萄糖代谢作用的部位以及 SIRT1 对这些作用的贡献。由于弓状核在中脑基底部下丘脑（MBH）中发挥着整合外周代谢对营养物质和激素反应的关键作用，我们研究了白藜芦醇的作用是否在 MBH 中发挥。
在基础胰岛索钳夹研究中，急性给予 Sprague Dawley（SD）雄性大鼠 MBH 或全身注射载体、白藜芦醇或 SIRT1 抑制剂。为了阐明 MBH 白藜芦醇调节肝葡萄糖生成的途径，我们使用短发夹 RNA（shRNA）沉默下丘脑 SIRT1 表达，用格列本脲抑制下丘脑三磷酸腺苷敏感性钾（K（ATP））通道，或选择性地横断迷走神经的肝支，同时给予 MBH 输注白藜芦醇。
我们的研究表明，急性给予 MBH 白藜芦醇或急性全身给予白藜芦醇可以显著改善胰岛素敏感性。使用细胞渗透性 SIRT1 抑制剂或 SIRT1-shRNA 选择性抑制下丘脑 SIRT1 可消除中枢和外周白藜芦醇对葡萄糖生成的影响。K（ATP）通道阻断和肝迷走神经切断术显著减弱了 MBH 白藜芦醇对肝葡萄糖生成的影响。此外，我们没有发现 MBH 白藜芦醇给药后下丘脑 AMPK 激活的证据。
综上所述，这些研究表明，白藜芦醇主要通过中枢 SIRT1 依赖途径改善葡萄糖稳态，并且 MBH 是白藜芦醇作用的主要部位。
