SEARCHCOHORTendocrinology, metabolism

cohort·endocrinology, metabolism, neuroscience, orthopedics, obesity medicine·PMC10132163

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

JCI Insight · 22 authors, 16 centres

AI SUMMARY

FIDELITY 100%

POPULATIONMice (C57BL/6J background) with Slc7a5 deficiency in LepR-expressing neurons (LepR-Cre Slc7a5^fl/fl^ mice), including HFD-fed and db/db mouse models

INTERVENTIONGenetic inactivation of Slc7a5 (encoding LAT1) in LepR-expressing neurons; selective reexpression of Slc7a5 in VMH neurons via AAV; genetic activation of mTORC1 by Tsc1 haploinsufficiency

COMPARISONControl littermates (Slc7a5^fl/fl^ or LepR-Cre mice); LepR-Cre Slc7a5^fl/fl^ mice with vs. without AAV-Slc7a5 reexpression; LepR-Cre Slc7a5^fl/fl^ mice with vs. without Tsc1^fl/+^ allele

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TL;DR

This study identifies l-type amino acid transporter 1 (LAT1) in hypothalamic leptin receptor-expressing (LepR-expressing) neurons as a key amino acid sensor that regulates both energy and bone homeostasis in mice. Mice lacking LAT1 in these neurons developed obesity, insulin resistance, and increased bone mass due to impaired leptin sensitivity and reduced sympathetic outflow. The findings suggest that the LAT1/mTORC1 signaling axis in the ventromedial hypothalamus represents a potential therapeutic target for obesity and osteoporosis.

Full summary

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**Background:** Hypothalamic neurons regulate body homeostasis by sensing hormones and primary nutrients such as amino acids. Branched-chain amino acids (BCAAs) have been linked to obesity and bone health, but the molecular mechanisms by which hypothalamic neurons detect amino acids remain unclear. l-type amino acid transporter 1 (LAT1, encoded by Slc7a5) facilitates cellular uptake of large neutral amino acids including BCAAs and activates mTORC1 signaling. This study investigated the role of LAT1 in leptin receptor-expressing (LepR-expressing) hypothalamic neurons in energy and bone homeostasis.

**Methods:** The authors used LepR-Cre Slc7a5^fl/fl^ mice to delete LAT1 specifically in LepR-expressing neurons. They assessed body weight, fat mass, glucose tolerance, insulin sensitivity, energy expenditure by indirect calorimetry, brown adipose tissue (BAT) function, and bone mass by μCT and histomorphometry. Amino acid uptake was measured using [^125^I]IMT, a LAT substrate. Leptin sensitivity was evaluated by STAT3 phosphorylation after systemic leptin administration. Sympathetic tone was assessed by serum/urine catecholamine levels and norepinephrine turnover assays. Selective reexpression of Slc7a5 in VMH neurons was achieved by stereotaxic AAV injection. mTORC1 involvement was tested by crossing with Tsc1^fl/+^ mice to genetically activate mTORC1.

**Key Results:** The hypothalamus exhibited LAT1-dependent amino acid uptake, which was significantly reduced in HFD-fed and db/db mice. Slc7a5 expression was highest among LAT family members in both mouse and human hypothalamus. LepR-Cre Slc7a5^fl/fl^ mice developed obesity by 8 weeks, with increased visceral and subcutaneous fat, adipocyte hypertrophy, and elevated leptin levels. [^125^I]IMT uptake was significantly decreased in the hypothalamus before obesity onset. Leucine, isoleucine, phenylalanine, tyrosine, and tryptophan levels were significantly decreased in the VMH of knockout mice. These mice exhibited impaired insulin sensitivity, reduced energy expenditure, decreased core body temperature, BAT whitening with lower mitochondrial content, and downregulation of thermogenic genes (Ucp1, Adrb3, Tfam, Cox7a). Food intake was unchanged, but locomotor activity was significantly decreased. Serum and urine epinephrine and norepinephrine were significantly lower both before (7 weeks) and after (24 weeks) obesity onset. Norepinephrine turnover was significantly decreased in BAT and soleus muscle at 7 weeks. Leptin-induced STAT3 phosphorylation was significantly impaired in LepR-expressing VMH neurons but not ARC neurons. Bone mass was significantly higher in the femur (but not vertebrae), with increased osteoblast number and bone formation rate and decreased osteoclast surface. Systemic isoproterenol (β-adrenoreceptor agonist) corrected the high bone mass phenotype. Selective reexpression of Slc7a5 in VMH neurons (but not ARC neurons) almost completely rescued body weight, fat accumulation, insulin sensitivity, and bone mass. Leptin-induced mTORC1 activation (pS6) was significantly suppressed in knockout mice. Genetic activation of mTORC1 by Tsc1 haploinsufficiency (LepR-Cre Slc7a5^fl/fl^ Tsc1^fl/+^ mice) ameliorated obesity, fat accumulation, insulin insensitivity, and high bone mass.

**Clinical Implications:** This study identifies LAT1 in LepR-expressing VMH neurons as a critical amino acid sensor that co-regulates energy and bone homeostasis through mTORC1 signaling and sympathetic outflow. The findings suggest that impaired amino acid sensing in the hypothalamus may contribute to obesity and osteoporosis. The LAT1/mTORC1 axis represents a potential novel therapeutic target for these common metabolic diseases. However, the study was conducted in mice, and human translation requires further investigation. The authors note that LAT1 is already being explored for cancer imaging and therapy, which may accelerate clinical translation.

PICO

PPOPULATION

Mice (C57BL/6J background) with Slc7a5 deficiency in LepR-expressing neurons (LepR-Cre Slc7a5^fl/fl^ mice), including HFD-fed and db/db mouse models

IINTERVENTION

Genetic inactivation of Slc7a5 (encoding LAT1) in LepR-expressing neurons; selective reexpression of Slc7a5 in VMH neurons via AAV; genetic activation of mTORC1 by Tsc1 haploinsufficiency

OOUTCOME

Body weight, fat mass, glucose tolerance, insulin sensitivity, energy expenditure, BAT function, leptin sensitivity (pSTAT3), sympathetic tone (catecholamines, norepinephrine turnover), bone mass (μCT, histomorphometry), amino acid levels in VMH

STUDY TYPE

cohort

SPECIALTY

endocrinology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

100% · A

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.