Better explicating the strengths and shortcomings of these models will help refine projections and improve transparency in the years ahead.
Image credit: Witsawat.S.
Edited by Stephen O’Rahilly, University of Cambridge, Cambridge, United Kingdom, and approved January 6, 2021 (received for review October 28, 2020)
Significance
Growth and differentiation factor-15 (GDF-15) acts through its receptor, GFRAL, expressed within the area postrema to reduce food intake and body weight. However, we do not yet understand GFRAL neuron transcriptional profile, regulation, the direct downstream target sites of GFRAL neurons, or the necessary cell types required for GDF-15 activity. Herein, we identify the genetic signature of GFRAL neurons and show that these cells are positively regulated by a number of aversive stimuli, project to both the nucleus of the solitary tract and more densely to the parabrachial nucleus, and that CGRPPBN neurons are required for the aversive and anorectic effects of GDF-15.
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 GfralCre and conditional GfralCreERT 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 GfralCre-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 (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 suppress nutrient uptake and absorption.
Footnotes
- ↵1To whom correspondence may be addressed. Email: seeleyrj{at}med.umich.edu.
Author contributions: P.V.S., H.F.-S., J.A., D.G., A.P., J.M.A., J.W., S.B.J., R.D.P., M.G.M., and R.J.S. designed research; P.V.S., H.F.-S., J.A., D.G., A.P., J.M.A., and J.W. performed research; S.B.J., D.P.O., and R.D.P. contributed new reagents/analytic tools; P.V.S., H.F.-S., J.A., D.G., A.P., A.C.R., and J.W. analyzed data; and P.V.S., H.F.-S., J.A., D.G., A.P., A.C.R., J.W., S.B.J., D.P.O., R.D.P., M.G.M., and R.J.S. wrote the paper.
Competing interest statement: S.B.J. is an employee of Novo Nordisk. D.P.O., M.G.M., and R.J.S. receive research support from Novo Nordisk. R.J.S. and M.G.M. receive research support from AstraZeneca. R.J.S. receives research support from Pfizer, Kintai, and Ionis. R.J.S. also serves as a paid consultant for Novo Nordisk, Kintai, Ionis, and Scohia. R.J.S. has equity positions in Zafgen and ReDesign Health. All other authors report no conflicts of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2021357118/-/DCSupplemental.
Data Availability.
TRAP-based sequencing data have been deposited in GenBank (accession number GSE160257) (34). All other study data are included in the article and/or supporting information.
Published under the PNAS license.
References
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GFRAL-expressing neurons suppress food intake via aversive pathways
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