Resveratrol activates duodenal Sirt1 to reverse insulin resistance in rats through a neuronal network
Resveratrol activates duodenal Sirt1 to reverse insulin resistance in rats through a neuronal network
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DOI：
10.1038/nm.3821
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发表时间：
2015-05-01
期刊：
影响因子：
82.9
通讯作者：
Lam, Tony K. T.
中科院分区：
文献类型：
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作者：
Cote, Clemence D.;Rasmussen, Brittany A.;Lam, Tony K. T.
在肥胖和糖尿病大鼠模型中，白藜芦醇可改善胰岛素敏感性并降低肝糖生成（HGP）（1-5），但这些抗糖尿病作用的潜在机制尚不清楚。一个被认为是白藜芦醇作用的关键特征的过程是在各种组织中激活烟酰胺腺嘌呤二核苷酸（NAD+）依赖的去乙酰化酶SIRT1 (SIRT1)（1,3,6-8）。然而，白藜芦醇的低生物利用度引发了口服白藜芦醇的抗糖尿病作用是否能直接作用于这些组织的问题（9,10）。我们在这里表明，急性十二指肠内输注白藜芦醇逆转了3天高脂肪饮食（HFD）诱导的十二指肠黏膜Sirt1蛋白水平的降低，同时也增强了胰岛素敏感性并降低了HGP。此外，我们发现，在正常饲料喂养的大鼠中，十二指肠特异性敲低Sirt1表达14 d足以诱导肝脏胰岛素抵抗。我们还发现，十二指肠作用的白藜芦醇的血糖调节作用需要激活该组织中的Sirt1和amp激活的蛋白激酶（Ampk）来启动肠-脑-肝神经元轴，从而改善下丘脑的胰岛素敏感性，进而降低HGP。除了十二指肠作用的白藜芦醇对急性3 d hfd喂养的胰岛素抵抗模型的影响外，我们还发现短期输注白藜芦醇到十二指肠可以降低另外两种胰岛素抵抗大鼠模型的HGP，即28 d hfd诱导的肥胖模型和烟酰胺(NA)-链脲佐菌素(STZ)- hfd诱导的轻度2型糖尿病模型。总之，这些研究强调了靶向十二指肠SIRT1逆转胰岛素抵抗和改善肥胖和糖尿病患者葡萄糖稳态的治疗相关性。
Resveratrol improves insulin sensitivity and lowers hepatic glucose production (HGP) in rat models of obesity and diabetes(1-5), but the underlying mechanisms for these antidiabetic effects remain elusive. One process that is considered a key feature of resveratrol action is the activation of the nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase sirtuin 1 (SIRT1) in various tissues(1,3,6-8). However, the low bioavailability of resveratrol raises questions about whether the antidiabetic effects of oral resveratrol can act directly on these tissues(9,10). We show here that acute intraduodenal infusion of resveratrol reversed a 3 d high fat diet (HFD)-induced reduction in duodenal-mucosal Sirt1 protein levels while also enhancing insulin sensitivity and lowering HGP. Further, we found that duodenum-specific knockdown of Sirt1 expression for 14 d was sufficient to induce hepatic insulin resistance in rats fed normal chow. We also found that the glucoregulatory role of duodenally acting resveratrol required activation of Sirt1 and AMP-activated protein kinase (Ampk) in this tissue to initiate a gut-brain-liver neuronal axis that improved hypothalamic insulin sensitivity and in turn, reduced HGP. In addition to the effects of duodenally acting resveratrol in an acute 3 d HFD-fed model of insulin resistance, we also found that short-term infusion of resveratrol into the duodenum lowered HGP in two other rat models of insulin resistance-a 28 d HFD-induced model of obesity and a nicotinamide (NA)-streptozotocin (STZ)-HFD-induced model of mild type 2 diabetes. Together, these studies highlight the therapeutic relevance of targeting duodenal SIRT1 to reverse insulin resistance and improve glucose homeostasis in obesity and diabetes.