2. Academic Validation
  3. GLP-2 prevents antipsychotics-induced metabolic dysfunction in mice

GLP-2 prevents antipsychotics-induced metabolic dysfunction in mice

  • Nat Metab. 2025 Apr;7(4):730-741. doi: 10.1038/s42255-025-01252-7.
Yanmin Peng # 1 2,  Chenzhang Feng # 3 4,  Shiyu Peng 5 6,  Ying Wang 3,  Qian Zhang 3 4,  Zhuolei Jiao 3 4,  Huateng Cao 3 4,  Shajin Huang 3,  Peihuang Tian 3 4,  Xiujia Sun 5,  Xiaohong Xu 7,  Yu Fu 8,  Ji Hu 9 10,  Zhe Zhang 11 12
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Psychotic Disorders, Brain Health Institute, National Center for Mental Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China. ameepeng@gmail.com.
  • 2 Institute of Neuroscience, State Key Laboratory of Neuroscience, Key Laboratory of Primate Neurobiology, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China. ameepeng@gmail.com.
  • 3 Institute of Neuroscience, State Key Laboratory of Neuroscience, Key Laboratory of Primate Neurobiology, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China.
  • 4 Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai, China.
  • 5 Shanghai Key Laboratory of Psychotic Disorders, Brain Health Institute, National Center for Mental Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 6 Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou, China.
  • 7 Institutes of Brain Science, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China.
  • 8 Institute of Molecular and Cell Biology, Agency for Science Technology and Research (A*STAR), Singapore, Singapore.
  • 9 Shanghai Key Laboratory of Psychotic Disorders, Brain Health Institute, National Center for Mental Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China. huji@shanghaitech.edu.cn.
  • 10 School of Life Science and Technology, ShanghaiTech University, Shanghai, China. huji@shanghaitech.edu.cn.
  • 11 Institute of Neuroscience, State Key Laboratory of Neuroscience, Key Laboratory of Primate Neurobiology, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China. zhezhang@ion.ac.cn.
  • 12 Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai, China. zhezhang@ion.ac.cn.
  • # Contributed equally.
PMID: 40114026 DOI: 10.1038/s42255-025-01252-7
Abstract

Antipsychotic drugs have severe metabolic side effects. Acute use can induce hypothermia, while chronic use often leads to weight gain and associated disorders. However, no treatment is currently available for drug-induced hypothermia, and weight control measures lack evidence for long-term effectiveness. Here we demonstrate that a glucagon-like peptide 2 analogue, teduglutide, effectively prevents olanzapine-induced hypothermia and weight gain, and restores glucose tolerance and Insulin sensitivity in mice. Mechanistically, olanzapine suppresses prodynorphin-expressing neurons in the ventromedial hypothalamus (VMHPdyn neurons) via serotonin receptor 2C, while teduglutide activates the same neuron population. Selective ablation of VMHPdyn neurons mimics olanzapine-induced side effects. More importantly, chemogenetic activation of VMHPdyn neurons abolishes olanzapine-induced hypothermia and excessive weight gain, although the psychotropic effects remain intact. Together, our data show that VMHPdyn neurons are the crucial mediator of antipsychotic-induced metabolic dysfunction and glucagon-like peptide 2 receptor agonism may be an effective target to mitigate both acute and chronic side effects.

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