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Research Articles, Cellular/Molecular

Ubiquitin-Specific Protease 2 in the Ventromedial Hypothalamus Modifies Blood Glucose Levels by Controlling Sympathetic Nervous Activation

Mayuko Hashimoto, Masaki Fujimoto, Kohtarou Konno, Ming-Liang Lee, Yui Yamada, Koya Yamashita, Chitoku Toda, Michio Tomura, Masahiko Watanabe, Osamu Inanami and Hiroshi Kitamura
Journal of Neuroscience 8 June 2022, 42 (23) 4607-4618; DOI: https://doi.org/10.1523/JNEUROSCI.2504-21.2022
Mayuko Hashimoto
1Laboratory of Veterinary Physiology, Department of Veterinary Medicine, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu 0698501, Japan
2Laboratory of Immunology, Faculty of Pharmacy, Osaka Ohtani University, Tondabayashi 5848450, Japan
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Masaki Fujimoto
3Laboratories of Radiation Biology and
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Kohtarou Konno
5Department of Anatomy and Embryology, Graduate School of Medicine, Hokkaido University, Sapporo 0600808, Japan
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Ming-Liang Lee
4Biochemistry, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 0600808, Japan
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Yui Yamada
1Laboratory of Veterinary Physiology, Department of Veterinary Medicine, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu 0698501, Japan
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Koya Yamashita
3Laboratories of Radiation Biology and
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Chitoku Toda
4Biochemistry, Faculty of Veterinary Medicine, Hokkaido University, Sapporo 0600808, Japan
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Michio Tomura
2Laboratory of Immunology, Faculty of Pharmacy, Osaka Ohtani University, Tondabayashi 5848450, Japan
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Masahiko Watanabe
5Department of Anatomy and Embryology, Graduate School of Medicine, Hokkaido University, Sapporo 0600808, Japan
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Osamu Inanami
3Laboratories of Radiation Biology and
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Hiroshi Kitamura
1Laboratory of Veterinary Physiology, Department of Veterinary Medicine, School of Veterinary Medicine, Rakuno Gakuen University, Ebetsu 0698501, Japan
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Abstract

Ubiquitin-specific protease 2 (USP2) participates in glucose metabolism in peripheral tissues such as the liver and skeletal muscles. However, the glucoregulatory role of USP2 in the CNS is not well known. In this study, we focus on USP2 in the ventromedial hypothalamus (VMH), which has dominant control over systemic glucose homeostasis. ISH, using a Usp2-specific probe, showed that Usp2 mRNA is present in VMH neurons, as well as other glucoregulatory nuclei, in the hypothalamus of male mice. Administration of a USP2-selective inhibitor ML364 (20 ng/head), into the VMH elicited a rapid increase in the circulating glucose level in male mice, suggesting USP2 has a suppressive role on glucose mobilization. ML364 treatment also increased serum norepinephrine concentration, whereas it negligibly affected serum levels of insulin and corticosterone. ML364 perturbated mitochondrial oxidative phosphorylation in neural SH-SY5Y cells and subsequently promoted the phosphorylation of AMP-activated protein kinase (AMPK). Consistent with these findings, hypothalamic ML364 treatment stimulated AMPKα phosphorylation in the VMH. Inhibition of hypothalamic AMPK prevented ML364 from increasing serum norepinephrine and blood glucose. Removal of ROS restored the ML364-evoked mitochondrial dysfunction in SH-SY5Y cells and impeded the ML364-induced hypothalamic AMPKα phosphorylation as well as prevented the elevation of serum norepinephrine and blood glucose levels in male mice. These results indicate hypothalamic USP2 attenuates perturbations in blood glucose levels by modifying the ROS–AMPK–sympathetic nerve axis.

SIGNIFICANCE STATEMENT Under normal conditions (excluding hyperglycemia or hypoglycemia), blood glucose levels are maintained at a constant level. In this study, we used a mouse model to identify a hypothalamic protease controlling blood glucose levels. Pharmacological inhibition of USP2 in the VMH caused a deviation in blood glucose levels under a nonstressed condition, indicating that USP2 determines the set point of the blood glucose level. Modification of sympathetic nervous activity accounts for the USP2-mediated glucoregulation. Mechanistically, USP2 mitigates the accumulation of ROS in the VMH, resulting in attenuation of the phosphorylation of AMPK. Based on these findings, we uncovered a novel glucoregulatory axis consisting of hypothalamic USP2, ROS, AMPK, and the sympathetic nervous system.

  • hypothalamus
  • mitochondria
  • reactive oxygen species
  • ubiquitin-specific protease 2
  • ventromedial hypothalamus

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The Journal of Neuroscience: 42 (23)
Journal of Neuroscience
Vol. 42, Issue 23
8 Jun 2022
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Ubiquitin-Specific Protease 2 in the Ventromedial Hypothalamus Modifies Blood Glucose Levels by Controlling Sympathetic Nervous Activation
Mayuko Hashimoto, Masaki Fujimoto, Kohtarou Konno, Ming-Liang Lee, Yui Yamada, Koya Yamashita, Chitoku Toda, Michio Tomura, Masahiko Watanabe, Osamu Inanami, Hiroshi Kitamura
Journal of Neuroscience 8 June 2022, 42 (23) 4607-4618; DOI: 10.1523/JNEUROSCI.2504-21.2022

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Ubiquitin-Specific Protease 2 in the Ventromedial Hypothalamus Modifies Blood Glucose Levels by Controlling Sympathetic Nervous Activation
Mayuko Hashimoto, Masaki Fujimoto, Kohtarou Konno, Ming-Liang Lee, Yui Yamada, Koya Yamashita, Chitoku Toda, Michio Tomura, Masahiko Watanabe, Osamu Inanami, Hiroshi Kitamura
Journal of Neuroscience 8 June 2022, 42 (23) 4607-4618; DOI: 10.1523/JNEUROSCI.2504-21.2022
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Keywords

  • hypothalamus
  • mitochondria
  • reactive oxygen species
  • ubiquitin-specific protease 2
  • ventromedial hypothalamus

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