Acute activation of central GLP-1 receptors enhances hepatic insulin action and insulin secretion in high-fat-fed, insulin resistant mice
Acute activation of central GLP-1 receptors enhances hepatic insulin action and insulin secretion in high-fat-fed, insulin resistant mice
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DOI：
10.1152/ajpendo.00409.2011
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发表时间：
2012-02-01
影响因子：
5.1
通讯作者：
Ayala, Julio E.
中科院分区：
文献类型：
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作者：
Burmeister, Melissa A.;Ferre, Tura;Ayala, Julio E.
Burmeister MA，Ferre T，Ayala JE，King EM，Holt RM，Ayala JE.中枢GLP-1受体的急性激活可增强高脂喂养的胰岛素抵抗小鼠的肝脏胰岛素作用和胰岛素分泌。Am J Physiol Endocrinol Metab 302：E334-E343，2012.首次发表于2011年11月15日; doi：10.1152/ajpendo.00409.2011.-胰高血糖素样肽-1（GLP-1）受体敲除（Glp 1 r（-/-））小鼠显示肝胰岛素作用受损。高脂（HF）喂养（Glp 1 r（-/-））小鼠表现出改善，而不是预期受损，肝胰岛素作用。这是由于脂肪生成基因表达和甘油三酯积累减少。本研究通过急性调节HF喂养野生型小鼠中的GLP-1 R作用克服了这些继发性适应。鉴于其作为肝脏胰岛素作用调节剂的作用，靶向了中枢GLP-1 R。我们假设，中枢GLP-1 R的急性抑制损害肝脏胰岛素作用，超出HF喂养的影响。我们进一步假设，中枢GLP-1 R的激活可改善HF喂养小鼠的肝脏胰岛素作用。使用高胰岛素正葡萄糖钳夹在清醒、无限制的小鼠中评估胰岛素作用。在钳夹期间，小鼠接受人工脑脊液、GLP-1或GLP-1 R拮抗剂exendin-9（Ex-9）的脑室内（icv）输注。侧脑室注射Ex-9可减弱胰岛素对肝脏葡萄糖生成的抑制作用，而icv GLP-1则可改善这种抑制作用，但两种治疗均不影响组织葡萄糖摄取。侧脑室注射GLP-1可增强肝脏Akt的激活，并抑制下丘脑AMP激活的蛋白激酶。高胰岛素血症期间，中枢GLP-1 R激活导致肝脏甘油三酯水平降低，但不影响肌肉、白色脂肪组织或血浆甘油三酯水平。响应口服而非静脉内葡萄糖挑战，中枢GLP-1 R的激活改善了葡萄糖耐量。这与较高的胰岛素水平有关。中枢GLP-1 R的抑制对口服或静脉葡萄糖耐量无影响。这些结果表明，抑制中枢GLP-1 R可使HF喂养小鼠的肝脏胰岛素作用恶化，但不影响全身葡萄糖稳态。与此相反，中枢GLP-1 R的激活通过增加胰岛素水平和增强肝脏胰岛素作用改善HF喂养小鼠的葡萄糖稳态。
Burmeister MA, Ferre T, Ayala JE, King EM, Holt RM, Ayala JE. Acute activation of central GLP-1 receptors enhances hepatic insulin action and insulin secretion in high-fat-fed, insulin resistant mice. Am J Physiol Endocrinol Metab 302: E334-E343, 2012. First published November 15, 2011; doi:10.1152/ajpendo.00409.2011.-Glucagon-like peptide-1 (GLP-1) receptor knockout (Glp1r(-/-)) mice exhibit impaired hepatic insulin action. High fat (HF)-fed (Glp1r(-/-)) mice exhibit improved, rather than the expected impaired, hepatic insulin action. This is due to decreased lipogenic gene expression and triglyceride accumulation. The present studies overcome these secondary adaptations by acutely modulating GLP-1R action in HF-fed wild-type mice. The central GLP-1R was targeted given its role as a regulator of hepatic insulin action. We hypothesized that acute inhibition of the central GLP-1R impairs hepatic insulin action beyond the effects of HF feeding. We further hypothesized that activation of the central GLP-1R improves hepatic insulin action in HF-fed mice. Insulin action was assessed in conscious, unrestrained mice using the hyperinsulinemic euglycemic clamp. Mice received intracerebroventricular (icv) infusions of artificial cerebrospinal fluid, GLP-1, or the GLP-1R antagonist exendin-9 (Ex-9) during the clamp. Intracerebro-ventricular Ex-9 impaired the suppression of hepatic glucose production by insulin, whereas icv GLP-1 improved it. Neither treatment affected tissue glucose uptake. Intracerebroventricular GLP-1 enhanced activation of hepatic Akt and suppressed hypothalamic AMP-activated protein kinase. Central GLP-1R activation resulted in lower hepatic triglyceride levels but did not affect muscle, white adipose tissue, or plasma triglyceride levels during hyperinsulinemia. In response to oral but not intravenous glucose challenges, activation of the central GLP-1R improved glucose tolerance. This was associated with higher insulin levels. Inhibition of the central GLP-1R had no effect on oral or intravenous glucose tolerance. These results show that inhibition of the central GLP-1R deteriorates hepatic insulin action in HF-fed mice but does not affect whole body glucose homeostasis. Contrasting this, activation of the central GLP-1R improves glucose homeostasis in HF-fed mice by increasing insulin levels and enhancing hepatic insulin action.