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ResearchIn-Press PreviewMetabolismNeuroscience Open Access | 10.1172/JCI193743

A single dorsal vagal complex circuit mediates the aversive and anorectic responses to GLP1R agonists

Warren T. Yacawych,1 Yi Wang,1 Guoxiang Zhou,2 Shad Hassan,3 Cagri Bodur,1 Elisabeth Walters,1 John G. Santinga,1 Frederike Sass,1 Martin deVaux,1 Stace Kernodle,4 Iris Wu,1 Jenny M. Brown,3 Dylan M. Belmont-Rausch,3 Alan C. Rupp,1 Abigail J. Tomlinson,1 Zitian Lin,2 Emma VanTongeren,1 Anna Secher,5 Kirsten Raun,6 Tune H. Pers,3 Randy J. Seeley,4 Martin G. Myers Jr.,1 and Weiwei Qiu2

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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

Find articles by Raun, K. in: PubMed | Google Scholar

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

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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

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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

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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

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Published September 15, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI193743.
Copyright © 2026, Yacawych et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published September 15, 2026 - Version history
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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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