Nat Metab :童青春和束刚/江青艳合作揭示“嘴馋”的中枢调控机制

2020-08-02 BioArt

本研究系统阐述了食欲引起肥胖的中枢调控机制,下丘脑弓状核部分GABA能神经元的随机兴奋即可引起食欲的增加,最终导致肥胖的发生。相反,依靠降低采食来控制体重,则需要抑制整个弓状核GABA神经元活性。

采食是动物进化过程中维持生长和发育的基础,当前由于人类文明进步大于自然进化速度,过多的能力摄入引起的肥胖已逐渐成为威胁人类健康的主要流行病之一。因此,如何通过控制饮食来降低体重已成为当前热门话题。但遗憾的是无法抵制食物的诱惑一直是阻碍降低体重的重要原因。

下丘脑弓状核作为食欲调控中枢,主要由GABA能神经元构成。目前普遍认为AgRP神经元是调控食欲高低的金标准,急性激活AgRP神经元可显着提高动物短期采食量;成年小鼠消除AgRP神经元则导致明显的厌食和体重减轻现象。但近年来研究发现,占据弓状核大部分的非AgRP GABA神经元(TH(Tyrosine Hydroxylase)、NOS1(Nitric Oxide Synthetase1)、PDX1(Pancreas-Duodenum Homeobox 1)等)在食欲和体重调节方面同样具有重要作用。此外,在幼年将AgRP神经元消除后并不影响动物的生长发育。因此,弓状核中AgRP神经元激活引起的食欲增加是否是引起肥胖的主要原因,非AgRP的GABA神经元在其中扮演什么样的角色,难以克服旺盛食欲的具体中枢调节机制是什么,目前并不清楚。

美国UT Health Science Center at Houston童青春课题组与华南农业大学束刚/江青艳课题组合作在Nature Metabolism杂志上发表了题为 Profound and Redundant Functions of Arcuate Neurons in Obesity Development 的论文,揭示弓状核GABA能神经元在动物肥胖发生过程中的关键作用。

作者首先通过特异性表达Na+通道NachBac来长期激活弓状核AgRP神经元或GABA能神经元,结果发现无论是激活AgRP还是GABA神经元都能引起类似于瘦素缺失小鼠(ob/ob)食欲旺盛和极度肥胖症状。而进一步对表达NaChBac的GABA神经元数量与小鼠体重分析发现小鼠的肥胖程度并不依赖于GABA神经元激活的数量,随机的单侧或双侧激活GABA神经元均能引起肥胖的发生。提示弓状核GABA神经元在肥胖调控中功能是重复的,这样导致只有其中一些神经元激活就足以导致肥胖。

随后作者以AgRPDTR小鼠特异性消除AgRP神经元为模型,发现无论是在特异性激活弓状核非AgRP的GABA神经元的普通小鼠,还是在消除AgRP神经元的ob/ob小鼠上,依旧出现与普通ob/ob小鼠类似性状。同时,分别向激活弓状核GABA神经元的正常小鼠和ob/ob小鼠脑室注射瘦素,并不能降低小鼠采食量和体重;相反,在缺失AgRP神经元的ob/ob小鼠中,瘦素依然能够显着降低其采食量和体重。上述结果说明无论是激活弓状核GABA神经元引起的肥胖,还是瘦素抑制肥胖的过程均不完全依赖于AgRP神经元的参与。

最后,为进一步证实GABA神经元在肥胖发生中的作用,作者分别向AgRP神经元或GABA神经元中表达K+通道Kir2.1来长期抑制这些神经元的活性。结果发现无论是普通小鼠还是ob/ob肥胖小鼠,只有长期双侧抑制几乎全部的弓状核GABA神经元才可以显着降低小鼠采食量和体重。但令人意外的是,即使是长期抑制几乎全部的AgRP神经元也并不影响小鼠采食量和体重。揭示弓状核GABA神经元在抑制动物食欲和体重方面起着关键作用。

本研究系统阐述了食欲引起肥胖的中枢调控机制,下丘脑弓状核部分GABA能神经元的随机兴奋即可引起食欲的增加,最终导致肥胖的发生。相反,依靠降低采食来控制体重,则需要抑制整个弓状核GABA神经元活性。弓状核GABA神经元在诱导肥胖的“冗余”以及降低体重的“必要”功能,充分解释了为什么减肥总是因为“嘴馋”而宣告失败,动物更容易产生对食物的渴望而不是厌恶。

原始出处:

Canjun Zhu, Zhiying Jiang, Yuanzhong Xu,et al.Profound and redundant functions of arcuate neurons in obesity development.Nat Metab. 2020 Jul 27. doi: 10.1038/s42255-020-0229-2.

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    2021-05-28 一闲
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    2021-06-17 liye789132251
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    2021-01-06 guojianrong
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    2020-08-03 14758c02m67暂无昵称

    学习了

    0

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    2020-08-02 肿肿

    机制研究离临床仍然有距离,不过与临床结合思考,仍然有帮助的,不能仅仅是纯临床思维,转化思维同样重要

    0

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