A single dorsal vagal complex circuit mediates the aversive and anorectic responses to GLP1R agonists
6 affiliations
- 1Department of Internal Medicine, University of Michigan, Ann Arbor, United States of America
- 2Zhejiang University-University of Edinburgh Institute, International Campus, Zhejiang University, Haining, China
- 3Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
- 4Department of Surgery, University of Michigan, Ann Arbor, United States of America
- 5Global Drug Discovery, Novo Nordisk A/S, Maløv, Denmark
- 6Research and Early Development, Novo Nordisk A/S, Maløv, Denmark
Abstract
GLP-1 receptor agonists (GLP1RAs) effectively reduce feeding to treat obesity, although nausea and other aversive side effects of these drugs can limit their use. Brainstem circuits that promote satiation and mediate the physiological control of body weight can be distinguished from those that cause aversion. It remains unclear whether brainstem Glp1r neurons contribute to the normal regulation of energy balance and whether GLP1RAs control appetite via circuits distinct from those that mediate aversive responses, however. Here, we silenced Glp1r neurons in the nucleus of the solitary tract or area postrema (NTSGlp1r or APGlp1r neurons, respectively) or restored their GLP1R signaling on an otherwise GLP1R-deficient background to determine physiological and pharmacological roles for each neuron population. Although NTSGlp1r neurons contributed to the normal restraint of food intake and body weight, they failed to mediate GLP1RA-dependent weight loss. In contrast, while we detected no role for APGlp1r neurons in physiological feeding, they mediated both the weight-lowering and aversive effects of GLP1RAs. Therefore, while non-aversive NTSGlp1r neurons control physiologic satiation they do not contribute to weight loss during GLP1RA treatment. Rather, APGlp1r neurons mediate both the weight-lowering and aversive effects of GLP1RAs, preventing the separation of their nauseating and weight-loss effects at a circuit level.
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BibTeX
@article{yacawych2026single,
title = {{A single dorsal vagal complex circuit mediates the aversive and anorectic responses to GLP1R agonists}},
author = {Warren T. Yacawych and Yi Wang and Guoxiang Zhou and Shad Hassan and Çağrı Bodur and Elisabeth Walters and John G. Santinga and Frederike Sass and Martin DeVaux and Stace Kernodle and Iris Wu and Jenny M. Brown and Dylan M. Belmont-Rausch and Alan C. Rupp and Abigail J. Tomlinson and Zitian Lin and Emma VanTongeren and Anna Secher and Kirsten Raun and Tune H. Pers and Randy J. Seeley and Martin Grosvenor Myers and Weiwei Qiu},
journal = {Journal of Clinical Investigation},
year = {2026},
month = sep,
doi = {10.1172/jci193743},
url = {https://doi.org/10.1172/jci193743},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - A single dorsal vagal complex circuit mediates the aversive and anorectic responses to GLP1R agonists
AU - Warren T. Yacawych
AU - Yi Wang
AU - Guoxiang Zhou
AU - Shad Hassan
AU - Çağrı Bodur
AU - Elisabeth Walters
AU - John G. Santinga
AU - Frederike Sass
AU - Martin DeVaux
AU - Stace Kernodle
AU - Iris Wu
AU - Jenny M. Brown
AU - Dylan M. Belmont-Rausch
AU - Alan C. Rupp
AU - Abigail J. Tomlinson
AU - Zitian Lin
AU - Emma VanTongeren
AU - Anna Secher
AU - Kirsten Raun
AU - Tune H. Pers
AU - Randy J. Seeley
AU - Martin Grosvenor Myers
AU - Weiwei Qiu
PY - 2026
DA - 2026/09/15
JO - Journal of Clinical Investigation
DO - 10.1172/jci193743
UR - https://doi.org/10.1172/jci193743
AB - GLP-1 receptor agonists (GLP1RAs) effectively reduce feeding to treat obesity, although nausea and other aversive side effects of these drugs can limit their use. Brainstem circuits that promote satiation and mediate the physiological control of body weight can be distinguished from those that cause aversion. It remains unclear whether brainstem Glp1r neurons contribute to the normal regulation of energy balance and whether GLP1RAs control appetite via circuits distinct from those that mediate aversive responses, however. Here, we silenced Glp1r neurons in the nucleus of the solitary tract or area postrema (NTSGlp1r or APGlp1r neurons, respectively) or restored their GLP1R signaling on an otherwise GLP1R-deficient background to determine physiological and pharmacological roles for each neuron population. Although NTSGlp1r neurons contributed to the normal restraint of food intake and body weight, they failed to mediate GLP1RA-dependent weight loss. In contrast, while we detected no role for APGlp1r neurons in physiological feeding, they mediated both the weight-lowering and aversive effects of GLP1RAs. Therefore, while non-aversive NTSGlp1r neurons control physiologic satiation they do not contribute to weight loss during GLP1RA treatment. Rather, APGlp1r neurons mediate both the weight-lowering and aversive effects of GLP1RAs, preventing the separation of their nauseating and weight-loss effects at a circuit level.
SN - 0021-9738
SN - 1558-8238
ER -