GLP-2 prevents antipsychotics-induced metabolic dysfunction in mice.

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.