Gfral-expressing Neurons Suppress Food Intake via Aversive Pathways

Paul V. Sabatini; Henriette Frikke‐Schmidt; Joe Arthurs; Desiree Gordian; Anita R. Patel; Alan C. Rupp; Jessica M. Adams; Jine Wang; Sebastian B. Jørgensen; David P. Olson; Richard D. Palmiter; Martin Grosvenor Myers; Randy J. Seeley

doi:10.1073/pnas.2021357118

NeuroscienceProceedings of the National Academy of SciencesFeb 15, 2021

Peer-reviewed journal article

Gfral-expressing Neurons Suppress Food Intake via Aversive Pathways

Paul V. Sabatini iD, Henriette Frikke‐Schmidt iD, Joe Arthurs iD, Desiree Gordian iD, Anita R. Patel iD, Alan C. Rupp iD, Jessica M. Adams iD, Jine Wang iD, Sebastian B. Jørgensen iD, David P. Olson iD, Richard D. Palmiter iD, Martin Grosvenor Myers iD, Randy J. Seeley iD

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Abstract

To determine the function and mechanisms of action for hindbrain neurons that express GFRAL, the receptor for the anorexigenic peptide, GDF-15, we generated Gfralcre and conditional GfralCreERT mice. While signals of infection or pathophysiologic states (rather than meal ingestion) stimulate GFRAL neurons, the artificial activation of GfralCre- expressing neurons inhibited feeding, decreased gastric emptying, and promoted a conditioned taste aversion (CTA). Additionally, activation of the smaller population of GFRAL neurons captured by the GfralCreERT allele decreased gastric emptying and produced a CTA without suppressing food intake, suggesting that GFRAL neurons primarily modulate gastric physiology and stimulate aversive responses. GFRAL neurons most strongly innervated the parabrachial nucleus (PBN), where they targeted CGRP-expressing (CGRPPBN) neurons. Silencing CGRPPBN neurons abrogated the aversive and anorexic effects of GDF-15. These findings suggest that GFRAL neurons link non-meal-associated, pathophysiologic signals to the aversive suppression of nutrient uptake and absorption.