Long-acting glucagon-like peptide-1 receptor agonists have direct access to and effects on pro-opiomelanocortin/cocaine- and amphetamine-stimulated transcript neurons in the mouse hypothalamus.
Long-acting glucagon-like peptide-1 receptor agonists have direct access to and effects on pro-opiomelanocortin/cocaine- and amphetamine-stimulated transcript neurons in the mouse hypothalamus.
复制标题
长效胰高血糖素样肽-1受体激动剂具有直接进入和对小鼠下丘脑中促蛋白酶素/可卡因和苯丙胺刺激的转录物神经元的影响和影响。
DOI：
10.1111/jdi.12463
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发表时间：
2016-04
影响因子：
3.2
通讯作者：
Pyke C
中科院分区：
文献类型：
--
作者：
Knudsen LB;Secher A;Hecksher-Sørensen J;Pyke C
利拉鲁肽是一种胰高血糖素样肽-1受体（GLP-1 R）激动剂，上市用于治疗2型糖尿病。除了降低血糖外，利拉鲁肽还能减轻体重，最近还被批准用于肥胖症适应症。急性期，GLP-1显著降低胃排空，先前认为该效应至少部分解释了对体重减轻的影响。然而，最近在人体和动物中进行的研究表明，GLP-1 R激动剂（如利拉鲁肽）可导致药理学浓度持续24小时/天，但对胃排空的影响较小;这种影响不太可能对食欲下降产生持久影响。利拉鲁肽已被证明对啮齿动物大脑的弓状核具有直接作用，激活阿黑皮素原神经元并增加可卡因和苯丙胺刺激的转录神经肽信使核糖核酸的水平，这与利拉鲁肽显示增加饱腹感的临床研究密切相关。然而，尽管缺乏胰岛素相关肽/神经肽Y神经元上的GLP-1 R，但利拉鲁肽也能够预防胰岛素相关肽和神经肽Y神经肽信使核糖核酸的饥饿相关增加，再次与临床研究密切相关，这些临床研究记录了服用利拉鲁肽时患者的饥饿感减轻。使用荧光标记的利拉鲁肽以及其他GLP-1 R激动剂的研究和使用单面照明显微镜的分析表明，此类中等大小的肽基化合物不仅可以直接进入脑的室周器官，还可以直接进入下丘脑的离散区域。长效GLP-1 R激动剂在下丘脑中的直接作用可能是了解GLP-1 R激动剂介导的体重减轻的重要新途径。
Liraglutide is a glucagon‐like peptide‐1 receptor (GLP‐1R) agonist marketed for the treatment of type 2 diabetes. Besides lowering blood glucose, liraglutide reduces bodyweight, and has recently also been approved for the obesity indication. Acutely, GLP‐1 markedly reduces gastric emptying, and this effect was previously believed to at least partly explain the effect on bodyweight loss. However, recent studies in both humans and animals have shown that GLP‐1R agonists, such as liraglutide, that lead to pharmacological concentrations for 24 h/day only have a minor effect on gastric emptying; such an effect is unlikely to have lasting effects on appetite reduction. Liraglutide has been shown to have direct effects in the arcuate nucleus of the rodent brain, activating pro‐opiomelanocortin neurons and increasing levels of the cocaine‐ and amphetamine‐stimulated transcript neuropeptide messenger ribonucleic acid, which correlate nicely to clinical studies where liraglutide was shown to increase feelings of satiety. However, despite the lack of a GLP‐1R on agouti‐related peptide/neuropeptide Y neurons, liraglutide also was able to prevent a hunger associated increase in agouti‐related peptide and neuropeptide Y neuropeptide messenger ribonucleic acid, again with a strong correlation to clinical studies that document reduced hunger feelings in patients while taking liraglutide. Studies using fluorescent labeled liraglutide, as well as other GLP‐1R agonists, and analysis using single‐plane illumination microscopy show that such medium‐sized peptide‐based compounds can directly access not only circumventricular organs of the brain, but also directly access discrete regions in the hypothalamus. The direct effects of long‐acting GLP‐1R agonists in the hypothalamus are likely to be an important new pathway in understanding GLP‐1R agonist mediated weight loss.