skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15

Abstract

Under homeostatic conditions, animals use well-defined hypothalamic neural circuits to help maintain stable body weight, by integrating metabolic and hormonal signals from the periphery to balance food consumption and energy expenditure1,2. In stressed or disease conditions, however, animals use alternative neuronal pathways to adapt to the metabolic challenges of altered energy demand3. Recent studies have identified brain areas outside the hypothalamus that are activated under these ‘non-homeostatic’ conditions4,5,6, but the molecular nature of the peripheral signals and brain-localized receptors that activate these circuits remains elusive. Here we identify glial cell-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) as a brainstem-restricted receptor for growth and differentiation factor 15 (GDF15). GDF15 regulates food intake, energy expenditure and body weight in response to metabolic and toxin-induced stresses; we show that Gfral knockout mice are hyperphagic under stressed conditions and are resistant to chemotherapy-induced anorexia and body weight loss. GDF15 activates GFRAL-expressing neurons localized exclusively in the area postrema and nucleus tractus solitarius of the mouse brainstem. It then triggers the activation of neurons localized within the parabrachial nucleus and central amygdala, which constitute part of the ‘emergency circuit’ that shapes feeding responses to stressful conditions7. GDF15 levels increase in response to tissue stress andmore » injury, and elevated levels are associated with body weight loss in numerous chronic human diseases8,9. By isolating GFRAL as the receptor for GDF15-induced anorexia and weight loss, we identify a mechanistic basis for the non-homeostatic regulation of neural circuitry by a peripheral signal associated with tissue damage and stress. These findings provide opportunities to develop therapeutic agents for the treatment of disorders with altered energy demand.« less

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; more »; ; ; ; ; ; ; ; ; ; ; ; ; ; « less
Publication Date:
Research Org.:
Brookhaven National Lab. (BNL), Upton, NY (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
OSTI Identifier:
1409576
Report Number(s):
BNL-114628-2017-JA¿¿¿
Journal ID: ISSN 0028-0836
DOE Contract Number:  
SC0012704
Resource Type:
Journal Article
Journal Name:
Nature (London)
Additional Journal Information:
Journal Volume: 550; Journal ID: ISSN 0028-0836
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES

Citation Formats

Hsu, Jer-Yuan, Crawley, Suzanne, Chen, Michael, Ayupova, Dina A., Lindhout, Darrin A., Higbee, Jared, Kutach, Alan, Joo, William, Gao, Zhengyu, Fu, Diana, To, Carmen, Mondal, Kalyani, Li, Betty, Kekatpure, Avantika, Wang, Marilyn, Laird, Teresa, Horner, Geoffrey, Chan, Jackie, McEntee, Michele, Lopez, Manuel, Lakshminarasimhan, Damodharan, White, Andre, Wang, Sheng-Ping, Yao, Jun, Yie, Junming, Matern, Hugo, Solloway, Mark, Haldankar, Raj, Parsons, Thomas, Tang, Jie, Shen, Wenyan D., Alice Chen, Yu, Tian, Hui, and Allan, Bernard B. Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15. United States: N. p., 2017. Web. doi:10.1038/nature24042.
Hsu, Jer-Yuan, Crawley, Suzanne, Chen, Michael, Ayupova, Dina A., Lindhout, Darrin A., Higbee, Jared, Kutach, Alan, Joo, William, Gao, Zhengyu, Fu, Diana, To, Carmen, Mondal, Kalyani, Li, Betty, Kekatpure, Avantika, Wang, Marilyn, Laird, Teresa, Horner, Geoffrey, Chan, Jackie, McEntee, Michele, Lopez, Manuel, Lakshminarasimhan, Damodharan, White, Andre, Wang, Sheng-Ping, Yao, Jun, Yie, Junming, Matern, Hugo, Solloway, Mark, Haldankar, Raj, Parsons, Thomas, Tang, Jie, Shen, Wenyan D., Alice Chen, Yu, Tian, Hui, & Allan, Bernard B. Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15. United States. doi:10.1038/nature24042.
Hsu, Jer-Yuan, Crawley, Suzanne, Chen, Michael, Ayupova, Dina A., Lindhout, Darrin A., Higbee, Jared, Kutach, Alan, Joo, William, Gao, Zhengyu, Fu, Diana, To, Carmen, Mondal, Kalyani, Li, Betty, Kekatpure, Avantika, Wang, Marilyn, Laird, Teresa, Horner, Geoffrey, Chan, Jackie, McEntee, Michele, Lopez, Manuel, Lakshminarasimhan, Damodharan, White, Andre, Wang, Sheng-Ping, Yao, Jun, Yie, Junming, Matern, Hugo, Solloway, Mark, Haldankar, Raj, Parsons, Thomas, Tang, Jie, Shen, Wenyan D., Alice Chen, Yu, Tian, Hui, and Allan, Bernard B. Wed . "Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15". United States. doi:10.1038/nature24042.
@article{osti_1409576,
title = {Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15},
author = {Hsu, Jer-Yuan and Crawley, Suzanne and Chen, Michael and Ayupova, Dina A. and Lindhout, Darrin A. and Higbee, Jared and Kutach, Alan and Joo, William and Gao, Zhengyu and Fu, Diana and To, Carmen and Mondal, Kalyani and Li, Betty and Kekatpure, Avantika and Wang, Marilyn and Laird, Teresa and Horner, Geoffrey and Chan, Jackie and McEntee, Michele and Lopez, Manuel and Lakshminarasimhan, Damodharan and White, Andre and Wang, Sheng-Ping and Yao, Jun and Yie, Junming and Matern, Hugo and Solloway, Mark and Haldankar, Raj and Parsons, Thomas and Tang, Jie and Shen, Wenyan D. and Alice Chen, Yu and Tian, Hui and Allan, Bernard B.},
abstractNote = {Under homeostatic conditions, animals use well-defined hypothalamic neural circuits to help maintain stable body weight, by integrating metabolic and hormonal signals from the periphery to balance food consumption and energy expenditure1,2. In stressed or disease conditions, however, animals use alternative neuronal pathways to adapt to the metabolic challenges of altered energy demand3. Recent studies have identified brain areas outside the hypothalamus that are activated under these ‘non-homeostatic’ conditions4,5,6, but the molecular nature of the peripheral signals and brain-localized receptors that activate these circuits remains elusive. Here we identify glial cell-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) as a brainstem-restricted receptor for growth and differentiation factor 15 (GDF15). GDF15 regulates food intake, energy expenditure and body weight in response to metabolic and toxin-induced stresses; we show that Gfral knockout mice are hyperphagic under stressed conditions and are resistant to chemotherapy-induced anorexia and body weight loss. GDF15 activates GFRAL-expressing neurons localized exclusively in the area postrema and nucleus tractus solitarius of the mouse brainstem. It then triggers the activation of neurons localized within the parabrachial nucleus and central amygdala, which constitute part of the ‘emergency circuit’ that shapes feeding responses to stressful conditions7. GDF15 levels increase in response to tissue stress and injury, and elevated levels are associated with body weight loss in numerous chronic human diseases8,9. By isolating GFRAL as the receptor for GDF15-induced anorexia and weight loss, we identify a mechanistic basis for the non-homeostatic regulation of neural circuitry by a peripheral signal associated with tissue damage and stress. These findings provide opportunities to develop therapeutic agents for the treatment of disorders with altered energy demand.},
doi = {10.1038/nature24042},
journal = {Nature (London)},
issn = {0028-0836},
number = ,
volume = 550,
place = {United States},
year = {2017},
month = {9}
}

Works referenced in this record:

Area postrema/nucleus of the solitary tract ablations: Analysis of the effects of hypophagia
journal, March 1984


The theoretical bases of indirect calorimetry: A review
journal, March 1988


Central nervous system control of metabolism
journal, November 2012


Gut-Brain Cross-Talk in Metabolic Control
journal, February 2017


Deciphering a neuronal circuit that mediates appetite
journal, March 2012

  • Wu, Qi; Clark, Michael S.; Palmiter, Richard D.
  • Nature, Vol. 483, Issue 7391
  • DOI: 10.1038/nature10899

The Buccaneer software for automated model building. 1. Tracing protein chains
journal, August 2006


The Anorectic Actions of the TGFβ Cytokine MIC-1/GDF15 Require an Intact Brainstem Area Postrema and Nucleus of the Solitary Tract
journal, June 2014


Genetic identification of a neural circuit that suppresses appetite
journal, October 2013

  • Carter, Matthew E.; Soden, Marta E.; Zweifel, Larry S.
  • Nature, Vol. 503, Issue 7474
  • DOI: 10.1038/nature12596

Anorexia–cachexia and obesity treatment may be two sides of the same coin: role of the TGF-b superfamily cytokine MIC-1/GDF15
journal, December 2015

  • Tsai, V. W. W.; Lin, S.; Brown, D. A.
  • International Journal of Obesity, Vol. 40, Issue 2
  • DOI: 10.1038/ijo.2015.242

The TGF-β superfamily cytokine, MIC-1/GDF15: A pleotrophic cytokine with roles in inflammation, cancer and metabolism
journal, August 2011


Features and development of Coot
journal, March 2010

  • Emsley, P.; Lohkamp, B.; Scott, W. G.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4
  • DOI: 10.1107/S0907444910007493

Cancer-induced anorexia and malaise are mediated by CGRP neurons in the parabrachial nucleus
journal, June 2017

  • Campos, Carlos A.; Bowen, Anna J.; Han, Sung
  • Nature Neuroscience, Vol. 20, Issue 7
  • DOI: 10.1038/nn.4574

REFMAC 5 dictionary: organization of prior chemical knowledge and guidelines for its use
journal, November 2004

  • Vagin, Alexei A.; Steiner, Roberto A.; Lebedev, Andrey A.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12
  • DOI: 10.1107/S0907444904023510

The effects on weight loss and gene expression in adipose and hepatic tissues of very-low carbohydrate and low-fat isoenergetic diets in diet-induced obese mice
journal, November 2016


GLP-1 Receptor Stimulation of the Lateral Parabrachial Nucleus Reduces Food Intake: Neuroanatomical, Electrophysiological, and Behavioral Evidence
journal, November 2014

  • Richard, Jennifer E.; Farkas, Imre; Anesten, Fredrik
  • Endocrinology, Vol. 155, Issue 11
  • DOI: 10.1210/en.2014-1248

Area postrema lesions produce feeding deficits in the rat: Effects of preoperative dieting and 2-deoxy-D-glucose
journal, November 1982


Characterization of a multicomponent receptor for GDNF
journal, July 1996

  • Treanor, James J. S.; Goodman, Laurie; de Sauvage, Frederic
  • Nature, Vol. 382, Issue 6586
  • DOI: 10.1038/382080a0

Molecular Modeling of the Extracellular Domain of the RET Receptor Tyrosine Kinase Reveals Multiple Cadherin-like Domains and a Calcium-binding Site
journal, July 2001

  • Anders, Jonas; Kjær, Svend; Ibáñez, Carlos F.
  • Journal of Biological Chemistry, Vol. 276, Issue 38
  • DOI: 10.1074/jbc.M104968200

The Structure of the Glial Cell Line-derived Neurotrophic Factor-Coreceptor Complex
journal, October 2008

  • Parkash, Vimal; Leppänen, Veli-Matti; Virtanen, Heidi
  • Journal of Biological Chemistry, Vol. 283, Issue 50
  • DOI: 10.1074/jbc.M802543200

Structure determination of an FMN reductase from Pseudomonas aeruginosa PA01 using sulfur anomalous signal
journal, March 2006

  • Agarwal, Rakhi; Bonanno, Jeffrey B.; Burley, Stephen K.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 62, Issue 4
  • DOI: 10.1107/S0907444906001600

Loss of GABAergic Signaling by AgRP Neurons to the Parabrachial Nucleus Leads to Starvation
journal, June 2009


Neurobiology of food intake in health and disease
journal, May 2014

  • Morton, Gregory J.; Meek, Thomas H.; Schwartz, Michael W.
  • Nature Reviews Neuroscience, Vol. 15, Issue 6
  • DOI: 10.1038/nrn3745

Experimental phasing with SHELXC / D / E : combining chain tracing with density modification
journal, March 2010

  • Sheldrick, George M.
  • Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4
  • DOI: 10.1107/S0907444909038360

The GDNF family: Signalling, biological functions and therapeutic value
journal, May 2002

  • Airaksinen, Matti S.; Saarma, Mart
  • Nature Reviews Neuroscience, Vol. 3, Issue 5
  • DOI: 10.1038/nrn812

Can anomalous signal of sulfur become a tool for solving protein crystal structures? 1 1Edited by I. A. Wilson
journal, May 1999

  • Dauter, Zbigniew; Dauter, Miroslawa; de La Fortelle, Eric
  • Journal of Molecular Biology, Vol. 289, Issue 1
  • DOI: 10.1006/jmbi.1999.2743

Structure of Artemin Complexed with Its Receptor GFRα3: Convergent Recognition of Glial Cell Line-Derived Neurotrophic Factors
journal, June 2006


The structure of GFRα1 domain 3 reveals new insights into GDNF binding and RET activation
journal, March 2004

  • Leppänen, Veli-Matti; Bespalov, Maxim M.; Runeberg-Roos, Pia
  • The EMBO Journal, Vol. 23, Issue 7
  • DOI: 10.1038/sj.emboj.7600174

Parabrachial CGRP Neurons Control Meal Termination
journal, May 2016


Identification, expression and functional characterization of the GRAL gene
journal, October 2005


Opposing Effects of Fasting Metabolism on Tissue Tolerance in Bacterial and Viral Inflammation
journal, September 2016


Excitatory Hindbrain–Forebrain Communication Is Required for Cisplatin-Induced Anorexia and Weight Loss
journal, December 2016


A Mutation at Tyrosine 1062 in MEN2A-Ret and MEN2B-Ret Impairs Their Transforming Activity and Association with Shc Adaptor Proteins
journal, July 1996

  • Asai, Naoya; Murakami, Hideki; Iwashita, Toshihide
  • Journal of Biological Chemistry, Vol. 271, Issue 30
  • DOI: 10.1074/jbc.271.30.17644

Cisplatin induces neuronal activation and increases central AMPA and NMDA receptor subunit gene expression in mice
journal, September 2014


Phaser crystallographic software
journal, July 2007

  • McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D.
  • Journal of Applied Crystallography, Vol. 40, Issue 4
  • DOI: 10.1107/S0021889807021206

Characterization of Growth-Differentiation Factor 15, a Transforming Growth Factor beta Superfamily Member Induced following Liver Injury
journal, May 2000


Tumor-induced anorexia and weight loss are mediated by the TGF-β superfamily cytokine MIC-1
journal, November 2007

  • Johnen, Heiko; Lin, Shu; Kuffner, Tamara
  • Nature Medicine, Vol. 13, Issue 11
  • DOI: 10.1038/nm1677