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首页> 外文期刊>Journal of neuroendocrinology >Ghrelin‐mediated improvements in the metabolic phenotype in the R6/2 mouse model of Huntington's disease
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Ghrelin‐mediated improvements in the metabolic phenotype in the R6/2 mouse model of Huntington's disease

机译：亨廷顿疾病R6 / 2小鼠模型中代谢表型的Ghrelin介导的改善

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Abstract Huntington's disease ( HD ) is a heritable neurodegenerative disorder, characterised?by metabolic disturbances, along with cognitive and psychiatric impairments.?Targeting metabolic HD dysfunction via the maintenance of body weight and fat mass and restoration of peripheral energy metabolism can improve the progression of neurological symptoms. In this respect, we focused on the therapeutic potential of the orexigenic peptide hormone ghrelin, which plays an important role in promoting a positive energy balance. In the present study, we found a significant disruption of circadian metabolic regulation in a R6/2 mouse HD model in the late stage of disease. Daily circadian rhythms of activity, energy expenditure, respiratory exchange ratio and feeding were strongly attenuated in R6/2 mice. During the rest phase, R6/2 mice had a higher total activity, elevated energy expenditure and excessive water consumption compared to control mice. We also found that, in the late stage of disease, R6/2 mice had ghrelin axis deficiency as a result of low circulating ghrelin levels, in addition to down‐regulation of the ghrelin receptor and several key signalling molecules in the hypothalamus, as well as a reduced responsiveness to exogenous peripheral ghrelin. We demonstrated that, in pre‐symptomatic mice, responsiveness to ghrelin is preserved. Chronic ghrelin treatment efficiently increased lean body mass and decreased the energy expenditure and fat utilisation of R6/2 mice in the early stage of disease. In addition, ghrelin treatment was also effective in the normalisation of drinking behaviour and the rest activity of these mice. Ghrelin treatment could provide a novel therapeutic possibility for delaying disease progression; however, deficiency in ghrelin receptor expression could limit its therapeutic potential in the late stage of disease.
机译：摘要亨廷顿的疾病（HD）是一种可遗传的神经退行性疾病，其特征在于？通过代谢紊乱，以及认知和精神障碍。通过维持体重和脂肪质量和外周能量代谢的恢复可以改善进展的代谢HD功能障碍。神经系统症状。在这方面，我们专注于丙烯酸肽激素Ghrelin的治疗潜力，这在促进阳性能量平衡方面发挥着重要作用。在本研究中，我们发现在疾病晚期R6 / 2小鼠HD模型中的昼夜昼夜代谢调节的显着破坏。每日昼夜活动，能源支出，呼吸交换比和饲养的节奏都在R6 / 2小鼠中强烈衰减。在静止阶段，与对照小鼠相比，R6 / 2小鼠具有更高的总活动，高能量消耗和过量的耗水量。我们还发现，在疾病的晚期阶段，除了较低的调节Ghrelin受体和下丘脑中的几个关键信号分子之外，R6 / 2小鼠还具有低循环的Ghrelin水平的Ghrelin轴缺乏。作为对外源外周Ghrelin的反应性降低。我们证明，在前症状的小鼠中，保留对Ghrelin的反应。慢性Ghrelin治疗有效地增加了瘦体重并降低了疾病早期阶段R6 / 2小鼠的能量消耗和脂肪利用率。此外，Ghrelin治疗也有效地在饮用行为的标准化和这些小鼠的静止活性方面有效。 Ghrelin治疗可以提供一种延迟疾病进展的新疗法可能性;然而，Ghrelin受体表达的缺乏可能会限制其治疗潜力在疾病的晚期。

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