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Journal Articles Nature Metabolism Year : 2022

Pharmacological targeting of glutamatergic neurons within the brainstem for weight reduction

Marc Schneeberger
  • Function : Author
  • PersonId : 1339596
Nicola L Brice
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Kyle Pellegrino
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Luca Parolari
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Jordan T Shaked
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Keith J Page
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François Marchildon
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Douglas W Barrows
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Thomas S Carroll
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Thomas Topilko
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Victoria M Mulligan
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Robert Newman
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Kevin Doyle
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Roland Bürli
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Daniel F Barker
Angela Glen
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María José Ortuño
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Alexander R Nectow
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Nicolas Renier
Paul Cohen
Mark Carlton
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Nathaniel Heintz
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Jeffrey M Friedman

Abstract

Food intake and body weight are tightly regulated by neurons within specific brain regions, including the brainstem, where acute activation of dorsal raphe nucleus (DRN) glutamatergic neurons expressing the glutamate transporter Vglut3 (DRN Vglut3 ) drive a robust suppression of food intake and enhance locomotion. Activating Vglut3 neurons in DRN suppresses food intake and increases locomotion, suggesting that modulating the activity of these neurons might alter body weight. Here, we show that DRN Vglut3 neurons project to the lateral hypothalamus (LHA), a canonical feeding center that also reduces food intake. Moreover, chronic DRN Vglut3 activation reduces weight in both leptin-deficient (ob/ob) and leptin-resistant diet-induced obese (DIO) male mice. Molecular profiling revealed that the orexin 1 receptor (Hcrtr1) is highly enriched in DRN Vglut3 neurons, with limited expression elsewhere in the brain. Finally, an orally bioavailable, highly selective Hcrtr1 antagonist (CVN45502) significantly reduces feeding and body weight in DIO. Hcrtr1 is also co-expressed with Vglut3 in the human DRN, suggesting that there might be a similar effect in human. These results identify a potential therapy for obesity by targeting DRN Vglut3 neurons while also establishing a general strategy for developing drugs for central nervous system disorders.
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hal-04410027 , version 1 (22-01-2024)

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Marc Schneeberger, Nicola L Brice, Kyle Pellegrino, Luca Parolari, Jordan T Shaked, et al.. Pharmacological targeting of glutamatergic neurons within the brainstem for weight reduction. Nature Metabolism, 2022, 4 (11), pp.1495-1513. ⟨10.1038/s42255-022-00677-8⟩. ⟨hal-04410027⟩
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