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 expenditure. In stressed or disease conditions, however, animals use alternative neuronal pathways to adapt to the metabolic challenges of altered energy demand. Recent studies have identified brain areas outside the hypothalamus that are activated under these 'non-homeostatic' conditions, 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 conditions. GDF15 levels increase in response to tissue stress and injury, and elevated levels are associated with body weight loss in numerous chronic human diseases. 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.
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GDF-15 regulates food intake, energy expenditure and body weight in response to metabolic and toxin-induced stress.
“which regulates food intake, energy expenditure and body weight in response to metabolic and toxin-induced stress79–81.”
From Genetic determinants of plasma protein levels in the Estonian population (2024) · cites this paper as [80]
Based on a proteomic analysis of plasma from 240 healthy, disease-free humans in the age range 22-93 years-old, GDF15 was identified as the protein most positively correlated with chronological age and also known to reduce appetite via an action in the hind-brain.
“Of additional interest and based on a proteomic analysis of the plasma from 240 healthy, disease-free, humans in the age range 22-93 years-old, GDF15 was identified as the protein most positively correlated with chronological age and also known to reduce appetite via an action in the hind-brain (82, 95).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [95]
GDF-15 binds exclusively to GFRAL and not to other TGF-β receptors or other GDNF family receptors.
“Metformin increases the secretion of GDF-15, which binds exclusively to glial cell-derived neurotrophic factor family receptor alpha-like (GFRAL).”
From GDF-15 as a Weight Watcher for Diabetic and Non-Diabetic People Treated With Metformin (2020) · cites this paper as [40]
GDF-15 forms a complex with GFRAL and RET on the cell surface, then triggers intracellular signaling through the ERK pathway.
“GDF-15 forms a complex with GFRAL and RET on the cell surface, then triggers an intracellular signaling cascade through the extracellular signal-related kinase (ERK) pathway (40, 113).”
From GDF-15 as a Weight Watcher for Diabetic and Non-Diabetic People Treated With Metformin (2020) · cites this paper as [40]
Exogenous administration of recombinant murine or human GDF-15 induces weight loss in different animal models.
“In line with these studies, exogenous administration of recombinant murine or human GDF-15 induced weight loss in different animal models (26, 32, 40, 41, 107).”
From GDF-15 as a Weight Watcher for Diabetic and Non-Diabetic People Treated With Metformin (2020) · cites this paper as [40]
GFRAL expression is limited to the brainstem and Gfral mRNA is highly expressed in the area postrema of mouse, rat, monkey and human.
“Unlike Gdf-15 which is expressed in diverse tissues, including kidney, liver, gut, muscle, adipose, and placenta, GFRAL expression is limited to the brainstem and Gfral mRNA is highly expressed in the area postrema of mouse, rat, monkey and human (39–41).”
From GDF-15 as a Weight Watcher for Diabetic and Non-Diabetic People Treated With Metformin (2020) · cites this paper as [40]
GDF-15 and GFRAL have emerged as regulators of energy balance and body weight.
“In addition to these functions, GDF-15 and its tissue-specific brainstem receptor, the glial cell-derived neurotrophic factor (GDNF) family receptor alpha-like (GFRAL), have emerged as regulators of energy balance and body weight (39–41).”
From GDF-15 as a Weight Watcher for Diabetic and Non-Diabetic People Treated With Metformin (2020) · cites this paper as [40]
GFRAL is exclusively expressed in the human brainstem and is responsible for the metabolic effects of GDF15 on regulating appetite.
“GFRAL is exclusively expressed in the human brainstem and is responsible for the metabolic effects of GDF15 on regulating appetite [201,215].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [215]
GDF15 binds with high affinity to GFRAL and its co-receptor RET, inducing phosphorylation of RET and downstream signaling through AKT, ERK1/2, and PLCγ pathways.
“GDF15 binds with high affinity to GFRAL and its co-receptor RET, which induces phosphorylation of RET, leading to downstream signaling through the AKT, ERK1/2, and phospholipase C (PLCγ) pathways [201,213,215].”
From Hepatokines and metabolism: Deciphering communication from the liver (2021) · cites this paper as [215]
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- Authors
- Hsu, J.-Y., Crawley, S., Chen, M., Ayupova, D. A., Lindhout, D. A., Higbee, J., Kutach, A., Joo, W., Gao, Z., Fu, D., To, C., Mondal, K., Li, B., Kekatpure, A., Wang, M., Laird, T., Horner, G., Chan, J., McEntee, M., Lopez, M., Lakshminarasimhan, D., White, A., Wang, S.-P., Yao, J., Yie, J., Matern, H., Solloway, M., Haldankar, R., Parsons, T., Tang, J., Shen, W. D., Alice Chen, Y., Tian, H., & Allan, B. B.
- Affiliations
- NGM Biopharmaceuticals (United States) (US)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Corresponding author
- Hsu, Jer-Yuan
- Allan, Bernard B.
- ORCID
- Venue
- Nature
- Published
- 2017-09-27
- Volume
- 550
- Issue
- 7675
- Pages
- 255-259
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2759628183
- Cited by
- 616
- References
- 41
- Citations by year
- 2026: 65 · 2025: 87 · 2024: 91 · 2023: 73 · 2022: 70 · 2021: 69 · 2020: 74 · 2019: 44 · 2018: 36 · 2017: 7
- FWCI
- 27.00
- Type
- journal article
- Language
- en
- Update notices
- erratum (2017-11-08)
- Open access
- closed
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Rheumatology › GDF15 and Related Biomarkers
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- GDF15, GFRAL, growth and differentiation factor 15, brainstem, appetite, chemotherapy-induced anorexia, cachexia, area postrema, nucleus tractus solitarius, parabrachial nucleus, stress response, energy expenditure, hyperphagia, hypothalamus
- MeSH terms
- Animals, Body Weight, Brain Stem, Eating, Energy Metabolism, Feeding Behavior, Female, Homeostasis, Male, Neurons, Stress, Psychological, Mice, Knockout, Glial Cell Line-Derived Neurotrophic Factor Receptors, Mice, Growth Differentiation Factor 15, Parabrachial Nucleus, Central Amygdaloid Nucleus
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