l-Type amino acid transporter 1 in hypothalamic neurons in mice maintains energy and bone homeostasis
Gyujin Park, Kazuya Fukasawa, Tetsuhiro Horie, Yusuke Masuo, Yuka Inaba, Takanori Tatsuno, Takanori Yamada, Kazuya Tokumura, Sayuki Iwahashi, Takashi Iezaki, Katsuyuki Kaneda, Yukio Kato, Yasuhito Ishigaki, Michihiro Mieda, Tomohiro Tanaka, Kazuma Ogawa, Hiroki Ochi, Shingo Sato, Yun-Bo Shi, Hiroshi Inoue, Hojoon Lee, Eiichi Hinoi
Gyujin Park, Kazuya Fukasawa, Tetsuhiro Horie, Yusuke Masuo, Yuka Inaba, Takanori Tatsuno, Takanori Yamada, Kazuya Tokumura, Sayuki Iwahashi, Takashi Iezaki, Katsuyuki Kaneda, Yukio Kato, Yasuhito Ishigaki, Michihiro Mieda, Tomohiro Tanaka, Kazuma Ogawa, Hiroki Ochi, Shingo Sato, Yun-Bo Shi, Hiroshi Inoue, Hojoon Lee, Eiichi Hinoi
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Research Article Bone biology Endocrinology

l-Type amino acid transporter 1 in hypothalamic neurons in mice maintains energy and bone homeostasis

Abstract

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.

Authors

Gyujin Park, Kazuya Fukasawa, Tetsuhiro Horie, Yusuke Masuo, Yuka Inaba, Takanori Tatsuno, Takanori Yamada, Kazuya Tokumura, Sayuki Iwahashi, Takashi Iezaki, Katsuyuki Kaneda, Yukio Kato, Yasuhito Ishigaki, Michihiro Mieda, Tomohiro Tanaka, Kazuma Ogawa, Hiroki Ochi, Shingo Sato, Yun-Bo Shi, Hiroshi Inoue, Hojoon Lee, Eiichi Hinoi

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Figure 1

Hypothalamus has a LAT1-dependent amino acid uptake system that is altered by metabolic states.

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Hypothalamus has a LAT1-dependent amino acid uptake system that is alter...
(A) Schematic diagram of the procedure for [125I]IMT uptake assay. (B and C) Brain tissues from wild-type mice at 8–12 weeks of age were incubated with [125I]IMT at 4°C or 37°C for 30 minutes in Hanks’ balanced salt solution (HBSS) buffer (B) (n = 5, ***P < 0.001, 2-tailed Student’s t test) or at 37°C for 30 minutes in HBSS buffer containing 30 μM JPH203 (C) (n = 10 or 11, ***P < 0.001, 2-tailed Student’s t test). (D and E) Quantification of mRNAs encoding LAT family in VMH (D) and ARC (E) of mice fed a normal chow diet (NC) at 8–12 weeks of age (n = 4, *P < 0.05, **P < 0.01, Kruskal-Wallis test post hoc Dunn’s test). TPM, transcripts per million. (F) Quantification of mRNAs encoding LAT family in human hypothalamus (n = 202, ***P < 0.001, Kruskal-Wallis test post hoc Dunn’s test). (G) Brain tissues from WT mice fed an NC or HFD (for 17 weeks, from 7 to 24 weeks of age) at 24 weeks of age were incubated with [125I]IMT at 37°C for 30 minutes in HBSS buffer (n = 5, *P < 0.05, 2-tailed Student’s t test). (H) Brain tissues from WT mice and db/db mice at 24 weeks of age were incubated with [125I]IMT at 37°C for 30 minutes in HBSS buffer (n = 5, ***P < 0.001, 2-tailed Student’s t test). (I) LAT1-dependent [125I]IMT uptake in brain tissues from WT mice and db/db mice at 24 weeks of age (n = 5, **P < 0.01, 2-tailed Student’s t test). (J and K) Quantification of Slc7a5 mRNA in VMH (J) and ARC (K) of mice fed an NC or HFD (from 5–6 to 8–12 weeks of age) at 8–12 weeks of age (n = 4, *P < 0.05, ***P < 0.001, Fisher’s exact test). All the mice used in this study were male. CPM, counts per million.