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Targeting Obesity and Cachexia: Identification of the GFRAL Receptor-MIC-1/GDF15 Pathway
Samuel N Breit1, Vicky Wang-Wei Tsai1, David A Brown1
1St Vincent's Centre for Applied Medical Research, St Vincent's Hospital and University of New South Wales, Sydney, New South Wales, 2010, Australia.
Abstract:
Macrophage inhibitory cytokine-1/growth differentiation factor 15 (MIC-1/GDF15) is a divergent transforming growth factor (TGFβ) superfamily cytokine implicated in biological and disease processes including metabolism, cancer, and chronic inflammation, but whose receptor has remained elusive. Four laboratories have recently identified GFRAL, an orphan receptor of the glial-derived neurotrophic factor (GDNF) receptor α family, as the receptor for MIC-1/GDF15, signaling though the coreceptor Ret. These data identify a new systemic to central nervous system (CNS) circuit that regulates metabolism in response to stress and which could be targeted to treat both severe obesity and anorexia/cachexia syndrome.
Insights
Researchers identified GFRAL as the receptor for Macrophage inhibitory cytokine-1/growth differentiation factor 15 (MIC-1/GDF15). This discovery reveals a new pathway regulating metabolism and offers potential treatments for obesity and anorexia.
Area of Science:
- Endocrinology
- Neuroscience
- Molecular Biology
Background:
- Macrophage inhibitory cytokine-1/growth differentiation factor 15 (MIC-1/GDF15) is a TGFβ superfamily cytokine involved in metabolism, cancer, and inflammation.
- The specific receptor for MIC-1/GDF15 has remained unidentified, limiting understanding of its biological functions.
Purpose of the Study:
- To identify the receptor for MIC-1/GDF15.
- To elucidate the signaling pathway of MIC-1/GDF15.
- To explore the therapeutic potential of the MIC-1/GDF15 pathway in metabolic disorders.
Main Methods:
- Utilized findings from four independent laboratories identifying GFRAL as the MIC-1/GDF15 receptor.
- Investigated the role of GFRAL in signaling through the coreceptor Ret.
- Analyzed the implications of this signaling circuit in metabolic regulation.
Main Results:
- GFRAL, an orphan receptor from the GDNF receptor α family, was identified as the specific receptor for MIC-1/GDF15.
- MIC-1/GDF15 signals via GFRAL and the coreceptor Ret.
- This interaction establishes a novel systemic-to-CNS circuit regulating metabolism.
Conclusions:
- The identification of GFRAL as the MIC-1/GDF15 receptor clarifies a critical aspect of this cytokine's function.
- This discovery opens new avenues for therapeutic interventions targeting obesity and anorexia/cachexia syndrome.
- The identified pathway highlights a key mechanism linking systemic signals to central nervous system metabolic control.
