Wang Penny Y T, Caspi Liora, Lam Carol K L, Chari Madhu, Li Xiaosong, Light Peter E, Gutierrez-Juarez Roger, Ang Michelle, Schwartz Gary J, Lam Tony K T
Toronto General Hospital Research Institute, University Health Network, Toronto M5G 1L7, Canada.
Nature. 2008 Apr 24;452(7190):1012-6. doi: 10.1038/nature06852. Epub 2008 Apr 9.
Energy and glucose homeostasis are regulated by food intake and liver glucose production, respectively. The upper intestine has a critical role in nutrient digestion and absorption. However, studies indicate that upper intestinal lipids inhibit food intake as well in rodents and humans by the activation of an intestine-brain axis. In parallel, a brain-liver axis has recently been proposed to detect blood lipids to inhibit glucose production in rodents. Thus, we tested the hypothesis that upper intestinal lipids activate an intestine-brain-liver neural axis to regulate glucose homeostasis. Here we demonstrate that direct administration of lipids into the upper intestine increased upper intestinal long-chain fatty acyl-coenzyme A (LCFA-CoA) levels and suppressed glucose production. Co-infusion of the acyl-CoA synthase inhibitor triacsin C or the anaesthetic tetracaine with duodenal lipids abolished the inhibition of glucose production, indicating that upper intestinal LCFA-CoAs regulate glucose production in the preabsorptive state. Subdiaphragmatic vagotomy or gut vagal deafferentation interrupts the neural connection between the gut and the brain, and blocks the ability of upper intestinal lipids to inhibit glucose production. Direct administration of the N-methyl-d-aspartate ion channel blocker MK-801 into the fourth ventricle or the nucleus of the solitary tract where gut sensory fibres terminate abolished the upper-intestinal-lipid-induced inhibition of glucose production. Finally, hepatic vagotomy negated the inhibitory effects of upper intestinal lipids on glucose production. These findings indicate that upper intestinal lipids activate an intestine-brain-liver neural axis to inhibit glucose production, and thereby reveal a previously unappreciated pathway that regulates glucose homeostasis.
能量和葡萄糖稳态分别由食物摄入和肝脏葡萄糖生成来调节。上肠道在营养物质的消化和吸收中起关键作用。然而，研究表明，上肠道脂质通过激活肠-脑轴也能抑制啮齿动物和人类的食物摄入。与此同时，最近有人提出存在一条脑-肝轴，可检测血脂以抑制啮齿动物的葡萄糖生成。因此，我们验证了这样一个假说，即上肠道脂质激活肠-脑-肝神经轴来调节葡萄糖稳态。在此我们证明，向上肠道直接注入脂质会增加上肠道长链脂肪酰辅酶A（LCFA-CoA）水平并抑制葡萄糖生成。将酰基辅酶A合酶抑制剂三辛素C或麻醉剂丁卡因与十二指肠脂质共同注入可消除对葡萄糖生成的抑制作用，这表明上肠道LCFA-CoA在吸收前状态下调节葡萄糖生成。膈下迷走神经切断术或肠道迷走神经传入阻滞会中断肠道与大脑之间的神经联系，并阻断上肠道脂质抑制葡萄糖生成的能力。将N-甲基-D-天冬氨酸离子通道阻滞剂MK-801直接注入第四脑室或肠道感觉纤维终止的孤束核，可消除上肠道脂质诱导的对葡萄糖生成的抑制作用。最后，肝迷走神经切断术消除了上肠道脂质对葡萄糖生成的抑制作用。这些发现表明，上肠道脂质激活肠-脑-肝神经轴以抑制葡萄糖生成，从而揭示了一条此前未被认识到的调节葡萄糖稳态的途径。
