Glucagon-Like Peptide-1 Receptor Agonist, Exendin-4, Regulates Feeding-Associated Neuropeptides in Hypothalamic Neurons in Vivo and in Vitro
Glucagon-Like Peptide-1 Receptor Agonist, Exendin-4, Regulates Feeding-Associated Neuropeptides in Hypothalamic Neurons in Vivo and in Vitro
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DOI：
10.1210/en.2011-1795
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发表时间：
2012-05-01
期刊：
影响因子：
4.8
通讯作者：
Belsham, Denise D.
中科院分区：
文献类型：
--
作者：
Dalvi, Prasad S.;Nazarians-Armavil, Anaies;Belsham, Denise D.
Exendin-4是一种长效胰高血糖素样肽-1受体（GLP-1 R）激动剂，通过其抑制胃排空、减少摄食量和诱导饱腹感的能力，是摄食行为的潜在调节剂。exendin-4激活GLP-1 R可诱导厌食症;然而，下丘脑（能量稳态的中枢调节因子）内exendin-4激活的神经肽能神经元的特定群体仍不清楚。本研究确定exendin-4是否调节下丘脑神经肽的表达，并探讨相关的信号转导机制。评价毒蜥外泌肽-4诱导的c-Fos免疫反应性的分布和数量，以确定在毒蜥外泌肽-4诱导的小鼠厌食症期间下丘脑核中α-黑素细胞刺激激素/阿黑皮素原、神经肽Y、神经降压素（NT）和生长素释放肽神经元的活化。此外，exendin-4的NT和ghrelin转录调控的行动进行了检查永生化下丘脑神经元。在由脑室内exendin-4诱导的厌食症中，弓状核中的α-黑素细胞刺激激素/阿黑皮素原和神经肽Y神经元被激活，同时室旁核中的NT表达神经元以及弓状核、室旁核和室周下丘脑中的ghrelin表达神经元被激活，这表明这些区域中的一个或多个区域中的神经元介导exendin-4的抑制作用。在下丘脑神经元细胞模型中，exendin-4增加cAMP，cAMP反应元件结合蛋白/激活转录因子1和c-Fos激活，并通过蛋白激酶A依赖的机制调节NT和ghrelin mRNA的表达，表明这些神经肽可能作为exendin-4作用的下游介质。这些发现提供了exendin-4激活中枢GLP-1 R与调节下丘脑NT和ghrelin之间先前未被认识的联系。进一步了解这种中心GLP-1 R激活可能会导致安全有效的治疗代谢疾病的治疗。（内分泌学153：2208-2222，2012）
Exendin-4, a long-acting glucagon-like peptide-1 receptor (GLP-1R) agonist, is a potential regulator of feeding behavior through its ability to inhibit gastric emptying, reduce food intake, and induce satiety. GLP-1R activation by exendin-4 induces anorexia; however, the specific populations of neuropeptidergic neurons activated by exendin-4 within the hypothalamus, the central regulator of energy homeostasis, remain unclear. This study determines whether exendin-4 regulates hypothalamic neuropeptide expression and explores the signaling mechanisms involved. The distribution and quantity of exendin-4-induced c-Fos immunoreactivity were evaluated to determine activation of alpha-melanocyte-stimulating hormone/proopiomelanocortin, neuropeptide Y, neurotensin (NT), and ghrelin neurons in hypothalamic nuclei during exendin-4-induced anorexia in mice. Additionally, exendin-4 action on NT and ghrelin transcript regulation was examined in immortalized hypothalamic neurons. With anorexia induced by intracerebroventricular exendin-4, alpha-melanocyte-stimulating hormone/proopiomelanocortin and neuropeptide Y neurons were activated in the arcuate nucleus, with simultaneous activation of NT-expressing neurons in the paraventricular nucleus, and ghrelin-expressing neurons in the arcuate nucleus, paraventricular nucleus, and periventricular hypothalamus, suggesting that neurons in one or more of these areas mediate the anorexic action of exendin-4. In the hypothalamic neuronal cell models, exendin-4 increased cAMP, cAMP response element-binding protein/activating transcription factor-1 and c-Fos activation, and via a protein kinase A-dependent mechanism regulated NT and ghrelin mRNA expression, indicating that these neuropeptides may serve as downstream mediators of exendin-4 action. These findings provide a previously unrecognized link between central GLP-1R activation by exendin-4 and the regulation of hypothalamic NT and ghrelin. Further understanding of this central GLP-1R activation may lead to safe and effective therapeutics for the treatment of metabolic disorders. (Endocrinology 153: 2208-2222, 2012)