Functional coupling between MC4R and Kir7.1 contributes to clozapine-induced hyperphagia
Li, L.; Hernandez, C. C.; Gimenez, L. E.; Xu, B.; Dahir, N. S.; Swati, F.; Birnbaum, S. G.; Cone, R. D.; Liu, C.
Show abstract
Most antipsychotic drugs (APDs) induce hyperphagia and weight gain. However, the neural mechanisms are poorly understood, partly due to challenges replicating their metabolic effects in rodents. Here, we report a new mouse model that recapitulates overeating induced by clozapine, a widely prescribed APD. Our study shows that clozapine boosts food intake by inhibiting melanocortin 4 receptor (MC4R) expressing neurons in the paraventricular nucleus of the hypothalamus. Interestingly, neither clozapine nor risperidone, another commonly used APD, affects receptor-ligand binding or the canonical Gs signaling of MC4R. Instead, they inhibit neuronal activity by enhancing the coupling between MC4R and Kir7.1, leading to the open state of the inwardly rectifying potassium channel. Deletion of Kir7.1 in Mc4r-Cre neurons prevents clozapine-induced weight gain, while treatment with a selective Kir7.1 blocker mitigates overeating in clozapine-fed mice. Our findings unveil a molecular pathway underlying the effect of APDs on feeding behavior and suggest its potential as a therapeutic target.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Nuclear Receptor 5A2 Regulation of Agrp underlies Olanzapine-induced Hyperphagia 96%
- LRRK2 mediates haloperidol-induced changes in indirect pathway striatal projection neurons 94%
- Sex-specific GABAergic microcircuits that switch vulnerability into resilience to stress and reverse the effects of chronic stress exposure 94%
Similar papers in this journal
- Chronic sodium bromide treatment relieves autistic-like behavioral deficits in three mouse models of autism 94%
- Perinatal THC Exposure via Lactation Induces Lasting Alterations to Social Behavior and Prefrontal Cortex Function in Rats at Adulthood 94%
- Cortical dopamine reduces the impact of motivational biases governing automated behaviour 93%
Similar papers in this journal
- Ibrutinib as a Potential Therapeutic for Cocaine Use Disorder 93%
- Estrogen signaling in the dorsal raphe regulates binge-like drinking in mice 93%
- adgrl3.1-deficient zebrafish show noradrenaline-mediated externalizing behaviors, and altered expression of externalizing disorder-candidate genes, suggesting functional targets for treatment 93%
Similar papers in this journal
- Direct serotonin release in humans shapes decision computations within aversive environments 93%
- Nucleus accumbens D1- and D2-expressing neurons control the balance between feeding and activity-mediated energy expenditure 93%
- Astrocyte glucocorticoid receptors mediate sex-specific changes in activity following stress 93%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.