Hypothalamic growth hormone receptor (GHR) controls hepatic glucose production in nutrient-sensing leptin receptor (LepRb) expressing neurons
Hypothalamic growth hormone receptor (GHR) controls hepatic glucose production in nutrient-sensing leptin receptor (LepRb) expressing neurons
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DOI：
10.1016/j.molmet.2017.03.001
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发表时间：
2017-05-01
影响因子：
8.1
通讯作者：
Sadagurski, Marianna
中科院分区：
文献类型：
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作者：
Cady, Gillian;Landeryou, Taylor;Sadagurski, Marianna
目的：GH/IGF-1轴在生长和代谢中起重要作用。GH和GH受体（GHR）在中枢神经系统（CNS）中具有活性，在调节代谢的几个方面至关重要。在下丘脑中，有大量的GH反应细胞，但GH信号在下丘脑神经元中的作用尚不清楚。先前的工作已经证明Ghr基因在LepRb神经元中高度表达。考虑到瘦素是一个关键的调节器的能量平衡，通过作用于瘦素受体（LepRb）表达的神经元，我们测试的假设，LepRb神经元代表一个重要的网站GHR信号控制身体homeostasis.Methods：为了确定GHR信号的重要性，在LepRb神经元，我们利用Cre/loxP技术消融GHR表达LepRb神经元（Lepr（EYFP德尔塔GHR））。通过将cre诱导型ROSA 26-EYFP小鼠上的Lepr（cre）与GHR（L/L）小鼠杂交来产生小鼠。结果：我们的研究结果表明，与GHR和LepRb共表达的网站包括ARH，DMH，和LHA神经元。Lepr（EYFP Delta GHR）小鼠中的瘦素作用没有改变;然而，在这些小鼠中，GH诱导的LepRb神经元中的pStat 5-IR显著降低。血清IGF-1和GH水平没有改变，我们没有发现GHR信号调节LepRb神经元的食物摄入和体重的证据。相反，LepRb神经元GHR信号减弱会损害肝脏胰岛素敏感性和外周脂质代谢。这是一个失败，以抑制EYFP Delta GHR小鼠Lepr（EYFP Delta GHR）的肝胰岛素信号转导和受损的hepatic eogenic基因的表达，这表明GHR-瘦素神经回路的存在，起着重要的作用，在GHR介导的葡萄糖代谢的调节，无论喂养。(C)2017作者由爱思唯尔有限公司出版。这是一个在CC BY-NC-ND许可证下的开放获取文章（http：//creativecommons.org/licenses/by-nc-nd/4.0/）。
Objective: The GH/IGF-1 axis has important roles in growth and metabolism. GH and GH receptor (GHR) are active in the central nervous system (CNS) and are crucial in regulating several aspects of metabolism. In the hypothalamus, there is a high abundance of GH-responsive cells, but the role of GH signaling in hypothalamic neurons is unknown. Previous work has demonstrated that the Ghr gene is highly expressed in LepRb neurons. Given that leptin is a key regulator of energy balance by acting on leptin receptor (LepRb)-expressing neurons, we tested the hypothesis that LepRb neurons represent an important site for GHR signaling to control body homeostasis.Methods: To determine the importance of GHR signaling in LepRb neurons, we utilized Cre/loxP technology to ablate GHR expression in LepRb neurons (Lepr(EYFP Delta GHR)). The mice were generated by crossing the Lepr(cre) on the cre-inducible ROSA26-EYFP mice to GHR(L/L) mice. Parameters of body composition and glucose homeostasis were evaluated.Results: Our results demonstrate that the sites with GHR and LepRb co-expression include ARH, DMH, and LHA neurons. Leptin action was not altered in Lepr(EYFP Delta GHR) mice; however, GH-induced pStat5-IR in LepRb neurons was significantly reduced in these mice. Serum IGF-1 and GH levels were unaltered, and we found no evidence that GHR signaling regulates food intake and body weight in LepRb neurons. In contrast, diminished GHR signaling in LepRb neurons impaired hepatic insulin sensitivity and peripheral lipid metabolism. This was paralleled with a failure to suppress expression of the gluconeogenic genes and impaired hepatic insulin signaling in Lepr(EYFP Delta GHR) mice.Conclusion: These findings suggest the existence of GHR-leptin neurocircuitry that plays an important role in the GHR-mediated regulation of glucose metabolism irrespective of feeding. (C) 2017 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).