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在能量和葡萄糖平衡中鉴定瘦素神经回路的基因
Jie Xu1, Christopher L Bartolome1,2, Cho Shing Low1,3
1Department of Neuroscience, Tufts University School of Medicine, Boston, MA, USA.
Nature
|April 20, 2018
概括
莱普
科学领域:
- 神经科学
- 内分泌学
- 代谢研究
背景情况:
- 但由于对神经回路的不完全理解,其临床应用是有限的.
- 假设的素点,即与相关的 (AGRP) 和亲梅拉诺科丁 (POMC) 神经元,尚未完全解释素的体内作用.
- 在AGRP或POMC神经元中使用选择性瘦素受体 (LEPR) 删除的先前研究未能完全复制瘦素缺乏的表型.
研究的目的:
- 系统地识别对瘦素敏感的神经元并澄清瘦素的主要神经点.
- 研究AGRP和POMC神经元在莱普调节能量平衡和葡萄糖平衡中的作用.
- 阐明白对目标神经元的急性和慢性作用的机制.
主要方法:
- 系统的,不偏见的研究素响应神经元在链毒素诱导的糖尿病小鼠.
- 在体内进行CRISPR-Cas9介导的LEPR基因切除.
- 化学基因对AGRP神经元进行操纵.
主要成果:
- AGRP神经元,而不是POMC神经元,对于瘦素调节能量平衡和葡萄糖平衡至关重要.
- 素缺乏可以消毒AGRP神经元,抑制这些神经元可以逆转糖尿病高和高血糖.
- 在AGRP神经元中通过CRISPR调节的LEPR删除精确地复制了Lepr小鼠的严重肥胖和糖尿病.
- 莱普对AGRP神经元的急性 (前突触GABA增强) 和慢性 (后突触ATP敏感通道激活) 抑制有不同的机制.
结论:
- AGRP神经元是瘦素对新陈代谢调节的主要直接神经点.
- 这项研究解决了长期以来关于瘦素主要神经点的问题,并阐明了它在代谢障碍中的作用.
- 这些发现为瘦素的作用和相关代谢疾病提供了神经生物学基础,为未来的治疗策略铺平了道路.
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