Pharmacological targeting of glutamatergic neurons within the brainstem for weight reduction
Year: 2022
Type: article
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 (DRNVglut3) 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 DRNVglut3 neurons project to the lateral hypothalamus (LHA), a canonical feeding center that also reduces food intake. Moreover, chronic DRNVglut3 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 DRNVglut3 neurons while also establishing a general strategy for developing drugs for central nervous system disorders.
Source: Nature Metabolism
Authors: Marc Schneeberger, Nicola L. Brice, Kyle Pellegrino, Luca Parolari, Jordan T. Shaked, Keith J. Page, François Marchildon, Douglas W. Barrows, Thomas S. Carroll, Thomas Topilko, Victoria M. Mulligan, Robert Newman, Kevin Doyle, Roland Bürli, Daniel F. Barker, Angela Glen, María José Ortuño, Alexander R. Nectow, Nicolas Renier, Paul Cohen, Mark Carlton, Nathaniel Heintz, Jeffrey M. Friedman
Language: English
Subfield: Endocrine and Autonomic Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $11,390
Funders: Howard Hughes Medical Institute, U.S. Department of Health and Human Services, JPB Foundation, National Alliance for Research on Schizophrenia and Depression, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Advancing Translational Sciences, H2020 European Research Council
Awards: G1137488791, G2451391735, Mechanisms of neuronal network remodeling in the adult mammalian brain, Understanding how the thermogenic response is orchestrated in the central nervous system, Understanding how the thermogenic response is orchestrated in the central nervous system, G8058190723, Developing, Demonstrating, and Disseminating Innovative Programs to Achieve Translational Success
OpenAlex ID: W4309668437