l-Type amino acid transporter 1 in hypothalamic neurons in mice maintains energy and bone homeostasis.
l-Type amino acid transporter 1 in hypothalamic neurons in mice maintains energy and bone homeostasis.
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DOI：
10.1172/jci.insight.154925
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发表时间：
2023-04-10
期刊：
影响因子：
8
通讯作者：
Hinoi, Eiichi
中科院分区：
文献类型：
--
作者：
Park, Gyujin;Fukasawa, Kazuya;Horie, Tetsuhiro;Masuo, Yusuke;Inaba, Yuka;Tatsuno, Takanori;Yamada, Takanori;Tokumura, Kazuya;Iwahashi, Sayuki;Iezaki, Takashi;Kaneda, Katsuyuki;Kato, Yukio;Ishigaki, Yasuhito;Mieda, Michihiro;Tanaka, Tomohiro;Ogawa, Kazuma;Ochi, Hiroki;Sato, Shingo;Shi, Yun-Bo;Inoue, Hiroshi;Lee, Hojoon;Hinoi, Eiichi
下丘脑神经元通过感知和整合关键激素和主要营养素(氨基酸、葡萄糖和脂质)水平的变化来调节身体的动态平衡。然而，使下丘脑神经元能够检测主要营养物质的分子机制仍然难以捉摸。在此，我们发现下丘脑瘦素受体表达神经元中的L氨基酸转运体1(LAT1)对全身能量和骨平衡具有重要作用。我们观察到LAT1依赖的氨基酸在下丘脑的摄取，这在肥胖和糖尿病的小鼠模型中受到了影响。在表达Lepr的神经元中缺乏LAT1(由溶质载体转运体7a5，Slc7a5编码)的小鼠表现出肥胖相关的表型和更高的骨量。在肥胖发生前，SLC7a5缺乏导致Lepr表达神经元的交感神经功能障碍和瘦素不敏感。重要的是，选择性地恢复表达Lepr的下丘脑腹内侧神经元中SLc7a5的表达，可以挽救表达Lepr的细胞中缺乏SLc7a5的小鼠的能量和骨稳态。雷帕霉素复合体-1的机械靶点(MTORC1)被发现是LAT1依赖的能量和骨内稳态调节的重要中介。这些结果表明，表达Lepr的神经元中的LAT1/mTORC1轴通过微调交感神经流出来控制能量和骨稳态，从而为下丘脑神经元对氨基酸的感知在体内稳态中的意义提供了体内证据。
Hypothalamic neurons regulate body homeostasis by sensing and integrating changes in the levels of key hormones and primary nutrients (amino acids, glucose, and lipids). However, the molecular mechanisms that enable hypothalamic neurons to detect primary nutrients remain elusive. Here, we identified l-type amino acid transporter 1 (LAT1) in hypothalamic leptin receptor–expressing (LepR-expressing) neurons as being important for systemic energy and bone homeostasis. We observed LAT1-dependent amino acid uptake in the hypothalamus, which was compromised in a mouse model of obesity and diabetes. Mice lacking LAT1 (encoded by solute carrier transporter 7a5, Slc7a5) in LepR-expressing neurons exhibited obesity-related phenotypes and higher bone mass. Slc7a5 deficiency caused sympathetic dysfunction and leptin insensitivity in LepR-expressing neurons before obesity onset. Importantly, restoring Slc7a5 expression selectively in LepR-expressing ventromedial hypothalamus neurons rescued energy and bone homeostasis in mice deficient for Slc7a5 in LepR-expressing cells. Mechanistic target of rapamycin complex-1 (mTORC1) was found to be a crucial mediator of LAT1-dependent regulation of energy and bone homeostasis. These results suggest that the LAT1/mTORC1 axis in LepR-expressing neurons controls energy and bone homeostasis by fine-tuning sympathetic outflow, thus providing in vivo evidence of the implications of amino acid sensing by hypothalamic neurons in body homeostasis.
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影响因子：
16.2
作者：
Dhillon, H;Zigman, JM;Lowelll, BB
通讯作者：
Lowelll, BB
DOI：
10.1083/jcb.201403009
发表时间：
2014-07-21
期刊：
The Journal of cell biology
影响因子：
--
作者：
Chen R;Zou Y;Mao D;Sun D;Gao G;Shi J;Liu X;Zhu C;Yang M;Ye W;Hao Q;Li R;Yu L
通讯作者：
Yu L
影响因子：
56.9
作者：
Cota, D;Proulx, K;Seeley, RJ
通讯作者：
Seeley, RJ
影响因子：
15.9
作者：
Adlanmerini, Marine;Nguyen, Hoang C. B.;Lazar, Mitchell A.
通讯作者：
Lazar, Mitchell A.
陷阱seq定义了下丘脑和脑干LEPB神经元的新型标记。
影响因子：
8.1
作者：
Allison MB;Patterson CM;Krashes MJ;Lowell BB;Myers MG Jr;Olson DP
通讯作者：
Olson DP