L-type amino acid transporter 1 in hypothalamic neurons regulates energy and bone homeostasis

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  • Fukasawa Kazuya
    Lab. Pharmacol., Dept. Bioactive Molecules, Gifu Pharmaceut. Univ.
  • Park Gyujin
    Lab. Pharmacol., Dept. Bioactive Molecules, Gifu Pharmaceut. Univ.
  • Hinoi Eiichi
    Lab. Pharmacol., Dept. Bioactive Molecules, Gifu Pharmaceut. Univ.

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Other Title
  • 視床下部アミノ酸トランスポーターLAT1によるエネルギー・骨代謝調節

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<p>Hypothalamic neurons in the central nervous system are pivotal regulators of body homeostasis by receiving and integrating perturbation in the levels of key hormones and primary nutrients (amino acid, glucose, and lipids). Here, we demonstrated that L-type amino acid transporter 1 (LAT1) in hypothalamic leptin receptor is important for systemic energy and bone homeostasis. The LAT1-dependent amino acid uptake system was functional in the hypothalamus, whose activity was impaired in a mouse model of obesity and diabetes. Mice whose LepR-expressing neurons lacked solute carrier transporter 7a5 (Slc7a5), which encodes LAT1, showed obesity-related phenotypes and higher bone mass. Slc7a5 deficiency caused sympathetic dysfunction and leptin insensitivity in LepR-expressing ventromedial hypothalamus (VMH) neurons prior to the onset of obesity. Importantly, adenoviral introduction of Slc7a5 selectively in LepR-expressing VMH neurons corrected abnormal energy and skeletal homeostasis. Mechanistic target of rapamycin complex-1 (mTORC1) was identified as a crucial mediator of LAT1-dependent regulation of energy and bone homeostasis. These results suggest the LAT1-mTORC1 axis in LepR-expressing VMH neurons controls energy and bone homeostasis by fine-tuning sympathetic outflow.</p>

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