Glp2 Prevents Antipsychoticsinduced Metabolic Dysfunction In Mice Yanmin Peng Chenzhang Feng Shiyu Peng Ying Wang Qian Zhang Zhuolei Jiao Huateng Cao Shajin Huang Peihuang Tian Xiujia Sun Xiaohong Xu Yu Fu Ji Hu Zhe Zhang by Yanmin Peng & Chenzhang Feng & Shiyu Peng & Ying Wang & Qian Zhang & Zhuolei Jiao & Huateng Cao & Shajin Huang & Peihuang Tian & Xiujia Sun & Xiaohong Xu & Yu Fu & Ji Hu & Zhe Zhang 101038/S42255025012527 instant download after payment.

Antipsychotic drugs have severe metabolic side efects. 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 efectiveness. Here we demonstrate that a glucagon-like peptide 2 analogue, teduglutide, efectively 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 efects. More importantly, chemogenetic activation of VMHPdyn neurons abolishes olanzapine-induced hypothermia and excessive weight gain, although the psychotropic efects 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 efective target to mitigate both acute and chronic side efects.