Amygdala astrocyte senescence drives stress-induced anxiety and hyperglycemia

  • Cell Metab. 2026 Jul 7;38(7):1385-1403.e10. doi: 10.1016/j.cmet.2026.03.006.
Aojie He  1 ,  Yufei Zhu  1 ,  Chensi Liang  1 ,  Shangmeng Huang  2 ,  Ziqi Yuan  1 ,  Shangchen Yang  1 ,  Yaoyi Chen  3 ,  Dan Can  1 ,  Aiyu Lei  1 ,  Huifang Li  1 ,  Lige Leng  4 ,  Jie Zhang  5
Affiliations
  • 1. Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China.
  • 2. Department of Geriatric, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China.
  • 3. Fujian Psychiatric Center, Fujian Clinical Research Center for Mental Disorders, Xiamen Xianyue Hospital, Xiamen, Fujian, China.
  • 4. Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China; Department of Pediatrics, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, Fujian, China; The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, Hebei, China; State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, Xiamen, China. Electronic address: [email protected].
  • 5. Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China; The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Shijiazhuang, Hebei, China. Electronic address: [email protected].
PMID: 41935525 DOI: 10.1016/j.cmet.2026.03.006
Abstract

Chronic stress (CS) exacerbates anxiety and hyperglycemia, emerging as a key risk factor for type 2 diabetes, yet the mechanism remains unclear. Here, we found that CS induces hyperglycemia and enhanced amygdaloid astrocytic senescence in mice. The amygdaloid astrocytic senescence was mediated by the reduction of Hexokinase 2 (HK2) driven by pre-B cell leukemia homeobox transcription factor 1 (PBX1). The astrocytic Hk2 deletion mice and amygdala-specific astrocytic Hk2 knockdown mice both display anxiety-like behaviors and hyperglycemia. The reduction of HK2 in astrocytes reduces L-serine synthesis and decreases the supply to neurons for the generation of D-serine by disrupting the astrocyte-neuron serine shuttle. Reduced neuronal D-serine level in the amygdala impaired the balance of sympathetic and parasympathetic amygdala-pancreas projections, leading to hyperglycemia. L-serine supplementation or dasatinib/quercetin administration to eliminate senescent cells alleviates both CS-induced neurobehaviors and peripheral hyperglycemia. Together, these findings reveal that HK2 in amygdaloid astrocytes mediates CS-induced neurobehaviors and hyperglycemia.

Keywords
astrocyte senescence; chronic stress; hexokinase 2; hyperglycemia; serine; sympathetic-parasympathetic imbalance.
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