The atypical antipsychotic risperidone targets hypothalamic melanocortin 4 receptors to cause weight gain.
Li LiEun-Seon YooXiujuan LiSteven C WylerXiameng ChenRong WanAmanda G ArnoldShari G BirnbaumLin JiaJong-Woo SohnChen LiuPublished in: The Journal of experimental medicine (2021)
Atypical antipsychotics such as risperidone cause drug-induced metabolic syndrome. However, the underlying mechanisms remain largely unknown. Here, we report a new mouse model that reliably reproduces risperidone-induced weight gain, adiposity, and glucose intolerance. We found that risperidone treatment acutely altered energy balance in C57BL/6 mice and that hyperphagia accounted for most of the weight gain. Transcriptomic analyses in the hypothalamus of risperidone-fed mice revealed that risperidone treatment reduced the expression of Mc4r. Furthermore, Mc4r in Sim1 neurons was necessary for risperidone-induced hyperphagia and weight gain. Moreover, we found that the same pathway underlies the obesogenic effect of olanzapine-another commonly prescribed antipsychotic drug. Remarkably, whole-cell patch-clamp recording demonstrated that risperidone acutely inhibited the activity of hypothalamic Mc4r neurons via the opening of a postsynaptic potassium conductance. Finally, we showed that treatment with setmelanotide, an MC4R-specific agonist, mitigated hyperphagia and obesity in both risperidone- and olanzapine-fed mice.
Keyphrases
- weight gain
- body mass index
- birth weight
- drug induced
- liver injury
- weight loss
- metabolic syndrome
- high fat diet induced
- single cell
- mouse model
- insulin resistance
- emergency department
- spinal cord
- combination therapy
- physical activity
- stem cells
- bone marrow
- cardiovascular disease
- spinal cord injury
- mesenchymal stem cells
- wild type
- cell therapy
- endothelial cells
- adverse drug
- oxidative stress
- preterm birth