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other·endocrinology, neurology, preclinical research, biomedical research·PMC10132163

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

JCI Insight · 22 authors, 16 centres

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TL;DR

This study used genetically modified mice to show that the amino acid transporter LAT1 in specific hypothalamic neurons is critical for regulating energy balance and bone mass. Mice lacking LAT1 in these neurons developed obesity and high bone mass due to impaired sympathetic signaling.

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The researchers generated mice with a targeted deletion of the *Slc7a5* gene (encoding LAT1) in leptin receptor-expressing (LepR-expressing) neurons. They found that *Slc7a5* deficiency led to reduced hypothalamic amino acid uptake, obesity-related phenotypes, increased bone mass, and impaired leptin sensitivity. Restoring *Slc7a5* expression specifically in LepR-expressing ventromedial hypothalamus neurons rescued these metabolic and skeletal abnormalities. The study identified mTORC1 as a key mediator of LAT1's regulatory effects. The findings provide in vivo evidence for the role of hypothalamic amino acid sensing in coordinating energy and bone homeostasis.

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other

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endocrinology

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ORIGINAL PAPER

PMC10132163

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

JCI Insight

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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.

CITATION EXPORT

Gyujin Park, Kazuya Fukasawa, Tetsuhiro Horie et al.. l-Type amino acid transporter 1 in hypothalamic neurons in mice maintains energy and bone homeostasis. JCI Insight. (2023). https://doi.org/10.1172/jci.insight.154925

AUTHORS

22 · 16 CENTRES

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

1Department of Bioactive Molecules, Laboratory Pharmacology, Gifu Pharmaceutical University, Gifu, Japan.
2Department of Neurobiology, Northwestern University, Evanston, Illinois, USA.
3Medical Research Institute, Kanazawa Medical University, Kahoku, Ishikawa, Japan.
4Faculty of Pharmacy, College of Medical, Pharmaceutical and Health, and
5Metabolism and Nutrition Research Unit, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa, Ishikawa, Japan.
6Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kanazawa, Ishikawa, Japan.
7Department of Integrative Neurophysiology, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan.
8Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.
9Laboratory of Clinical Analytical Sciences, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kanazawa, Ishikawa, Japan.
10Discovering Molecular Probes Research Unit, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa, Ishikawa, Japan.
11Department of Rehabilitation for Motor Functions, Research Institute, National Rehabilitation Center for Persons with Disabilities, Tokorozawa, Saitama, Japan.
12Center for Innovative Cancer Treatment, Tokyo Medical and Dental University, Tokyo, Japan.
13Section on Molecular Morphogenesis, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, Maryland, USA.
14Department of Physiology and Metabolism, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan.
15United Graduate School of Drug Discovery and Medical Information Sciences, and
16Division of Innovative Modality Development, Center for One Medicine Innovative Translational Research, Gifu University, Gifu, Japan.