Thyroid hormone modulates glucose production via a sympathetic pathway from the hypothalamic paraventricular nucleus to the liver
Thyroid hormone modulates glucose production via a sympathetic pathway from the hypothalamic paraventricular nucleus to the liver
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DOI：
10.1073/pnas.0805355106
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发表时间：
2009-04-07
影响因子：
11.1
通讯作者：
Kalsbeek, Andries
中科院分区：
文献类型：
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作者：
Klieverik, Lars P.;Janssen, Sarah F.;Kalsbeek, Andries
甲亢增加内源性葡萄糖生成(EGP)，并诱导肝脏胰岛素抵抗。我们最近发现，这些改变可以通过选择性的肝交感神经和副交感神经去神经来调节，指出甲状腺激素对葡萄糖代谢的神经调节作用。在这里，我们研究了中枢三碘甲腺原氨酸(T-3)给药对EGP的影响。采用稳定同位素稀释法测定静脉注射前后的EGP。甲状腺功能正常大鼠推注T-3或赋形剂。为研究下丘脑自主前神经元的作用，在双侧室旁核(PVN)内进行T-3微透析2 h，最后将PVN内的T-3微透析与选择性肝交感神经切断相结合，以阐明交感神经系统在所观察的代谢变化中的参与。T-3微透析室旁核内EGP增加11+/-4%(P=0.020)，而赋形剂治疗组EGP下降5+/-8%(Ns)(T-3vs.Veh，P=0.030)。T-3微透析后血糖升高29+/-5%(P=0.0001)，而赋形剂组大鼠血糖升高8+/-3%(T-3vs.Veh，P=0.003)。静脉注射后也观察到类似的效果。T-3管理。PVN T-3微透析的效果与血浆T-3、胰岛素、高血糖素和皮质酮无关。但选择性肝交感神经节切除术完全阻断T-3微透析对EGP的影响。我们的结论是，刺激正常甲状腺大鼠PVN中的T-3敏感神经元，通过向肝脏的交感神经投射增加了EGP，而不依赖于循环中的糖调节激素。这是甲状腺激素调节肝脏葡萄糖代谢的一条独特的中枢途径。
Thyrotoxicosis increases endogenous glucose production (EGP) and induces hepatic insulin resistance. We have recently shown that these alterations can be modulated by selective hepatic sympathetic and parasympathetic denervation, pointing to neurally mediated effects of thyroid hormone on glucose metabolism. Here, we investigated the effects of central triiodothyronine (T-3) administration on EGP. We used stable isotope dilution to measure EGP before and after i.c.v. bolus infusion of T-3 or vehicle in euthyroid rats. To study the role of hypothalamic preautonomic neurons, bilateral T-3 microdialysis in the paraventricular nucleus (PVN) was performed for 2 h. Finally, we combined T-3 microdialysis in the PVN with selective hepatic sympathetic denervation to delineate the involvement of the sympathetic nervous system in the observed metabolic alterations. T-3 microdialysis in the PVN increased EGP by 11 +/- 4% (P = 0.020), while EGP decreased by 5 +/- 8%(ns) in vehicle-treated rats (T-3 vs. Veh, P = 0.030). Plasma glucose increased by 29 +/- 5% (P = 0.0001) after T-3 microdialysis versus 8 +/- 3% in vehicle-treated rats (T-3 vs. Veh, P = 0.003). Similar effects were observed after i.c.v. T-3 administration. Effects of PVN T-3 microdialysis were independent of plasma T-3, insulin, glucagon, and corticosterone. However, selective hepatic sympathectomy completely prevented the effect of T-3 microdialysis on EGP. We conclude that stimulation of T-3-sensitive neurons in the PVN of euthyroid rats increases EGP via sympathetic projections to the liver, independently of circulating glucoregulatory hormones. This represents a unique central pathway for modulation of hepatic glucose metabolism by thyroid hormone.