2. Academic Validation
  3. d-Glucosamine induces circadian phase delay by promoting BMAL1 degradation through AMPK/mTOR pathway

d-Glucosamine induces circadian phase delay by promoting BMAL1 degradation through AMPK/mTOR pathway

  • Life Sci. 2023 May 10;325:121765. doi: 10.1016/j.lfs.2023.121765.
Zeqi Li 1,  Bo Fu 1,  Aili Wei 1,  Yanchen Wu 2,  Ming Huang 3,  Enhao Zhang 4,  Bo Cui 1,  Bo Wang 5,  Hui Peng 6
Affiliations

Affiliations

  • 1 Department of Operational Medicine, Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China.
  • 2 Department of Operational Medicine, Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China; School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
  • 3 School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
  • 4 School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
  • 5 State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China. Electronic address: [email protected].
  • 6 Department of Operational Medicine, Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China; School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 210009, China; School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China. Electronic address: [email protected].
PMID: 37169147 DOI: 10.1016/j.lfs.2023.121765
Abstract

Circadian rhythms are closely linked to the metabolic network through circadian feedback regulation. The hexosamine biosynthetic pathway (HBP) is a branch of glucose metabolism that affects circadian rhythms through the O-linked N-acetylglucosamine modification (O-GlcNAcylation) of clock proteins. Here, we found out that, among the downstream metabolites regulated by d-glucosamine (GlcN) in HBP salvage pathway, only GlcN is able to induce circadian phase delay both in vitro and in vivo. Mechanistic studies indicated that the phase-shift induced by GlcN is independent of O-GlcNAcylation. Instead, GlcN selectively up-regulates p-AMPK activity, leading to the inhibition of mTOR signaling pathway, and thus down-regulation of p-BMAL1 both in human cell line and mouse tissues. Moreover, GlcN promoted BMAL1 degradation via Proteasome pathway. These findings reveal a novel molecular mechanism of GlcN in regulating clock phase and suggest the therapeutic potential of GlcN as new use for an old drug in the future treatment of shift work and circadian misalignment.

Keywords

AMPK/mTOR signaling; BMAL1; Circadian phase; Glucosamine; O-GlcNAcylation.

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