GFRAL-expressing neurons suppress food intake via aversive pathways

Paul V Sabatini; 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 Jr; Randy J Seeley

doi:10.1073/pnas.2021357118

GFRAL-expressing neurons suppress food intake via aversive pathways

Proc Natl Acad Sci U S A. 2021 Feb 23;118(8):e2021357118. doi: 10.1073/pnas.2021357118.

Authors

Paul V Sabatini¹, Henriette Frikke-Schmidt², Joe Arthurs^{3

4}, Desiree Gordian¹, Anita Patel², Alan C Rupp¹, Jessica M Adams^{5

6}, Jine Wang^{1

7}, Sebastian Beck Jørgensen⁸, David P Olson⁵, Richard D Palmiter^{3

4}, Martin G Myers Jr¹, Randy J Seeley⁹

Affiliations

¹ Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109.
² Department of Surgery, University of Michigan, Ann Arbor, MI 48109.
³ Howard Hughes Medical Institute and Department of Biochemistry, University of Washington, Seattle, WA 98115.
⁴ Howard Hughes Medical Institute and Department of Genome Sciences, University of Washington, Seattle, WA 98115.
⁵ Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109.
⁶ School of Biological Sciences, Illinois State University, Normal, IL 61790.
⁷ College of Medical Science, China Three Gorges University, 43002 Yichang, China.
⁸ Diabetes Research Unit, Novo Nordisk A/S, 2760 Maaloev, Denmark.
⁹ Department of Surgery, University of Michigan, Ann Arbor, MI 48109; seeleyrj@med.umich.edu.

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 Gfral^Cre and conditional Gfral^CreERT 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 Gfral^Cre -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^PBN) neurons. Silencing CGRP^PBN 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.

Keywords: CGRP; GDF-15; GFRAL; area postrema; obesity.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Avoidance Learning / drug effects*
Body Weight
Eating / drug effects*
Feeding Behavior / drug effects*
Female
Glial Cell Line-Derived Neurotrophic Factor Receptors / genetics
Glial Cell Line-Derived Neurotrophic Factor Receptors / metabolism*
Growth Differentiation Factor 15 / pharmacology*
Male
Mice
Neurons / drug effects
Neurons / physiology*
Parabrachial Nucleus / drug effects
Parabrachial Nucleus / physiology*
Rats
Rats, Long-Evans

Substances

Glial Cell Line-Derived Neurotrophic Factor Receptors
Growth Differentiation Factor 15

Abstract

Publication types

MeSH terms

Substances

Grants and funding