ArticleThe Journal of experimental medicine2021
The atypical antipsychotic risperidone targets hypothalamic melanocortin 4 receptors to cause weight gain.
Article in The Journal of experimental medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
22 citing papers in PubMed, 32 citations in OpenAlex.
- Melanocortin-4 Receptor Gene Variants and Weight Change Following Switch to Integrase Inhibitor-Based Antiretroviral Therapy.Open forum infectious diseases · 2025Trial
- Identification of serum metabolic traits of AIWG in first-episode schizophrenia patients.BMC psychiatry · 2024Trial
- Functional coupling between MC4R and Kir7.1 contributes to clozapine-induced weight gain in female mice.Nature communications · 2026Article
- Structural and functional studies of inward rectifier Kir7.1 and its regulation by the Melanocortin-4 receptor.Nature communications · 2026Article
- The hypothalamus as a therapeutic target: Towards novel approaches for managing antipsychotic-induced weight gain.Reviews in endocrine & metabolic disorders · 2026Review
- Genomic Insights Into Risperidone Treatment Outcomes in Children and Adolescents: Experience From a Psychiatric Hospital Serving Rural Youth.Clinical pharmacology and therapeutics · 2026Article
- Review
- Predictive Role of Serotonin Receptor (5HTR2A) and Dopamine Receptor (DRD2) gene polymorphisms in risperidone-induced weight gain and hyperprolactinemia in patients with schizophrenia.European journal of clinical pharmacology · 2025Article
- GLP-2 prevents antipsychotics-induced metabolic dysfunction in mice.Nature metabolism · 2025Article
- Article
- Real-world pharmacovigilance of risperidone: Analysis based on FAERS reports from physicians and pharmacists.PloS one · 2025Article
- Metabolic Side Effects of Risperidone in Pediatric Patients with Neurological Disorders: A Prospective Cohort Study.Journal of clinical medicine · 2024Article
- Hyperleptinemia contributes to antipsychotic drug-associated obesity and metabolic disorders.Science translational medicine · 2023Article
- The unique structural characteristics of the Kir 7.1 inward rectifier potassium channel: a novel player in energy homeostasis control.American journal of physiology. Cell physiology · 2023Review
- Metabolic biomarkers of risperidone-induced weight gain in drug-naïve patients with schizophrenia.Frontiers in psychiatry · 2023Article
- Delineating a serotonin 1B receptor circuit for appetite suppression in mice.The Journal of experimental medicine · 2022Article
- Effect of Co-Treatment of Olanzapine with SEP-363856 in Mice Models of Schizophrenia.Molecules (Basel, Switzerland) · 2022Article
- Deciphering Risperidone-Induced Lipogenesis by Network Pharmacology and Molecular Validation.Frontiers in psychiatry · 2022Article
- Recent advances in neuropeptide-related omics and gene editing: Spotlight on NPY and somatostatin and their roles in growth and food intake of fish.Frontiers in endocrinology · 2022Review
- The role of hypothalamic endoplasmic reticulum stress in schizophrenia and antipsychotic-induced weight gain: A narrative review.Frontiers in neuroscience · 2022Review
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.