The atypical antipsychotic risperidone targets hypothalamic melanocortin 4 receptors to cause weight gain.
Animals
Antipsychotic Agents
/ pharmacology
Female
Hyperphagia
/ metabolism
Hypothalamus
/ drug effects
Male
Metabolic Syndrome
/ metabolism
Mice
Mice, Inbred C57BL
Models, Animal
Neurons
/ drug effects
Obesity
/ metabolism
Olanzapine
/ pharmacology
Potassium
/ metabolism
Receptor, Melanocortin, Type 4
/ metabolism
Risperidone
/ pharmacology
Synaptic Potentials
/ drug effects
Transcriptome
/ drug effects
Weight Gain
/ drug effects
alpha-MSH
/ analogs & derivatives
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
05 07 2021
05 07 2021
Historique:
received:
23
11
2020
revised:
17
02
2021
accepted:
02
04
2021
entrez:
12
5
2021
pubmed:
13
5
2021
medline:
13
10
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33978701
pii: 212095
doi: 10.1084/jem.20202484
pmc: PMC8126977
pii:
doi:
Substances chimiques
Antipsychotic Agents
0
MC4R protein, mouse
0
Receptor, Melanocortin, Type 4
0
setmelanotide
0
alpha-MSH
581-05-5
Risperidone
L6UH7ZF8HC
Olanzapine
N7U69T4SZR
Potassium
RWP5GA015D
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIDDK NIH HHS
ID : F32 DK116427
Pays : United States
Organisme : NIAAA NIH HHS
ID : K01 AA024809
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK114036
Pays : United States
Informations de copyright
© 2021 Li et al.
Déclaration de conflit d'intérêts
Disclosures: The authors declare no competing interests exist.
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