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GFRAL-expressing neurons suppress food intake via aversive pathways.

Citation
Sabatini, P., et al. “Gfral-Expressing Neurons Suppress Food Intake Via Aversive Pathways.”. Proceedings Of The National Academy Of Sciences Of The United States Of America.
Center University of Michigan
Author Paul Sabatini V, Henriette Frikke-Schmidt, Joe Arthurs, Desiree Gordian, Anita Patel, Alan C Rupp, Jessica M Adams, Jine Wang, Sebastian Beck Jørgensen, David P Olson, Richard D Palmiter, Martin G Myers, Randy J Seeley
Keywords CGRP, GDF-15, GFRAL, area postrema, obesity
Abstract

The TGFβ cytokine family member, GDF-15, reduces food intake and body weight and represents a potential treatment for obesity. Because the brainstem-restricted expression pattern of its receptor, GDNF Family Receptor α-like (GFRAL), presents an exciting opportunity to understand mechanisms of action for area postrema neurons in food intake; we generated and conditional mice to visualize and manipulate GFRAL neurons. We found infection or pathophysiologic states (rather than meal ingestion) stimulate GFRAL neurons. TRAP-Seq analysis of GFRAL neurons revealed their expression of a wide range of neurotransmitters and neuropeptides. Artificially activating -expressing neurons inhibited feeding, decreased gastric emptying, and promoted a conditioned taste aversion (CTA). GFRAL neurons most strongly innervate the parabrachial nucleus (PBN), where they target CGRP-expressing (CGRP) neurons. Silencing CGRP neurons abrogated the aversive and anorexic effects of GDF-15. These findings suggest that GFRAL neurons link non-meal-associated pathophysiologic signals to suppress nutrient uptake and absorption.

Year of Publication
2021
Journal
Proceedings of the National Academy of Sciences of the United States of America
Volume
118
Issue
8
Date Published
02/2021
ISSN Number
1091-6490
DOI
10.1073/pnas.2021357118
Alternate Journal
Proc Natl Acad Sci U S A
PMID
33593916
PMCID
PMC7923658
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