Gfral-expressing Neurons Suppress Food Intake via Aversive Pathways

Sabatini, P. V.; Henriette Frikke-Schmidt, H.; Arthurs, J.; Gordian, D.; Patel, A.; Adams, J. M.; Wang, J.; Beck Jorgensen, S.; Olson, D. P.; Palmiter, R. D.; Myers, M. G.; Seeley, R. J.

doi:10.1101/2020.05.11.088773

bioRxiv · 10.1101/2020.05.11.088773

Gfral-expressing Neurons Suppress Food Intake via Aversive Pathways

Sabatini, P. V.·Henriette Frikke-Schmidt, H.·Arthurs, J.·Gordian, D.·Patel, A.·Adams, J. M.·Wang, J.·Beck Jorgensen, S.·Olson, D. P.·Palmiter, R. D.·Myers, M. G.·Seeley, R. J.

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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.

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Sabatini, P. V., Henriette Frikke-Schmidt, H., Arthurs, J., Gordian, D., Patel, A., Adams, J. M., Wang, J., Beck Jorgensen, S., Olson, D. P., Palmiter, R. D., Myers, M. G., Seeley, R. J.. 2020-05-13. Gfral-expressing Neurons Suppress Food Intake via Aversive Pathways. https://doi.org/10.1101/2020.05.11.088773

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