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ResearchIn-Press PreviewEndocrinologyNeuroscience Open Access | 10.1172/jci.insight.160891

Sustained inhibition of NPY/AgRP neuronal activity by FGF1

Eunsang Hwang,1 Jarrad M. Scarlett,2 Arian F. Baquero,3 Camdin Bennett,3 Yanbin Dong,1 Dominic Chau,1 Jenny M. Brown,4 Aaron J. Mercer,3 Thomas H. Meek,3 Kevin L. Grove,3 Bao Anh N. Phan,4 Gregory J. Morton,4 Kevin W. Williams,1 and Michael W. Schwartz4

1Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, United States of America

2Department of Pediatric Gastroenterology and Hepatology, Seattle Children’s Hospital, Seattle, United States of America

3Obesity Research, Novo Nordisk Research Center Seattle, Seattle, United States of America

4Department of Medicine, University of Washington Medicine Diabetes Institute, Seattle, United States of America

Find articles by Hwang, E. in: JCI | PubMed | Google Scholar

1Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, United States of America

2Department of Pediatric Gastroenterology and Hepatology, Seattle Children’s Hospital, Seattle, United States of America

3Obesity Research, Novo Nordisk Research Center Seattle, Seattle, United States of America

4Department of Medicine, University of Washington Medicine Diabetes Institute, Seattle, United States of America

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1Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, United States of America

2Department of Pediatric Gastroenterology and Hepatology, Seattle Children’s Hospital, Seattle, United States of America

3Obesity Research, Novo Nordisk Research Center Seattle, Seattle, United States of America

4Department of Medicine, University of Washington Medicine Diabetes Institute, Seattle, United States of America

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1Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, United States of America

2Department of Pediatric Gastroenterology and Hepatology, Seattle Children’s Hospital, Seattle, United States of America

3Obesity Research, Novo Nordisk Research Center Seattle, Seattle, United States of America

4Department of Medicine, University of Washington Medicine Diabetes Institute, Seattle, United States of America

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1Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, United States of America

2Department of Pediatric Gastroenterology and Hepatology, Seattle Children’s Hospital, Seattle, United States of America

3Obesity Research, Novo Nordisk Research Center Seattle, Seattle, United States of America

4Department of Medicine, University of Washington Medicine Diabetes Institute, Seattle, United States of America

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1Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, United States of America

2Department of Pediatric Gastroenterology and Hepatology, Seattle Children’s Hospital, Seattle, United States of America

3Obesity Research, Novo Nordisk Research Center Seattle, Seattle, United States of America

4Department of Medicine, University of Washington Medicine Diabetes Institute, Seattle, United States of America

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1Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, United States of America

2Department of Pediatric Gastroenterology and Hepatology, Seattle Children’s Hospital, Seattle, United States of America

3Obesity Research, Novo Nordisk Research Center Seattle, Seattle, United States of America

4Department of Medicine, University of Washington Medicine Diabetes Institute, Seattle, United States of America

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1Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, United States of America

2Department of Pediatric Gastroenterology and Hepatology, Seattle Children’s Hospital, Seattle, United States of America

3Obesity Research, Novo Nordisk Research Center Seattle, Seattle, United States of America

4Department of Medicine, University of Washington Medicine Diabetes Institute, Seattle, United States of America

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1Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, United States of America

2Department of Pediatric Gastroenterology and Hepatology, Seattle Children’s Hospital, Seattle, United States of America

3Obesity Research, Novo Nordisk Research Center Seattle, Seattle, United States of America

4Department of Medicine, University of Washington Medicine Diabetes Institute, Seattle, United States of America

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1Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, United States of America

2Department of Pediatric Gastroenterology and Hepatology, Seattle Children’s Hospital, Seattle, United States of America

3Obesity Research, Novo Nordisk Research Center Seattle, Seattle, United States of America

4Department of Medicine, University of Washington Medicine Diabetes Institute, Seattle, United States of America

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1Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, United States of America

2Department of Pediatric Gastroenterology and Hepatology, Seattle Children’s Hospital, Seattle, United States of America

3Obesity Research, Novo Nordisk Research Center Seattle, Seattle, United States of America

4Department of Medicine, University of Washington Medicine Diabetes Institute, Seattle, United States of America

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1Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, United States of America

2Department of Pediatric Gastroenterology and Hepatology, Seattle Children’s Hospital, Seattle, United States of America

3Obesity Research, Novo Nordisk Research Center Seattle, Seattle, United States of America

4Department of Medicine, University of Washington Medicine Diabetes Institute, Seattle, United States of America

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1Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, United States of America

2Department of Pediatric Gastroenterology and Hepatology, Seattle Children’s Hospital, Seattle, United States of America

3Obesity Research, Novo Nordisk Research Center Seattle, Seattle, United States of America

4Department of Medicine, University of Washington Medicine Diabetes Institute, Seattle, United States of America

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1Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas, United States of America

2Department of Pediatric Gastroenterology and Hepatology, Seattle Children’s Hospital, Seattle, United States of America

3Obesity Research, Novo Nordisk Research Center Seattle, Seattle, United States of America

4Department of Medicine, University of Washington Medicine Diabetes Institute, Seattle, United States of America

Find articles by Schwartz, M. in: JCI | PubMed | Google Scholar

Published August 2, 2022 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.160891.
Copyright © 2022, Hwang 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 August 2, 2022 - Version history
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Abstract

In rodent models of type 2 diabetes (T2D), central administration of fibroblast growth factor 1 (FGF1) normalizes elevated blood glucose levels in a manner that is sustained for weeks or months. Increased activity of NPY/AgRP neurons in the hypothalamic arcuate nucleus (ARC) is implicated in the pathogenesis of hyperglycemia in these animals, and the ARC is a key brain area for the antidiabetic action of FGF1. We therefore sought to determine whether FGF1 inhibits NPY/AgRP neurons, and if so whether this inhibitory effect is sufficiently durable to offer a feasible explanation for sustained diabetes remission induced by central administration of FGF1. Here we show that FGF1 inhibits ARC NPY/AgRP neuron activity, both after icv injection in vivo and when applied ex vivo in a slice preparation, and that the underlying mechanism involves increased input from presynaptic GABAergic neurons. Following central administration, the inhibitory effect of FGF1 on NPY/AgRP neurons is also highly durable, lasting for at least two weeks. To our knowledge, no precedent for such a prolonged inhibitory effect exists. Future studies are warranted to determine whether NPY/AgRP neuron inhibition contributes to the sustained antidiabetic action elicited by icv FGF1 injection in rodent models of T2D.  

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