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Review
. 2019 Jun:198:46-58.
doi: 10.1016/j.pharmthera.2019.02.008. Epub 2019 Feb 18.

Growth differentiation factor 15 (GDF15): A survival protein with therapeutic potential in metabolic diseases

Seung Joon Baek  1 , Thomas Eling  2
Affiliations
Review

Growth differentiation factor 15 (GDF15): A survival protein with therapeutic potential in metabolic diseases

Seung Joon Baek et al. Pharmacol Ther. 2019 Jun.

Abstract

Growth Differentiation Factor 15 (GDF15), also known as NSAID activated gene-1 (NAG-1), is associated with a large number of biological processes and diseases, including cancer and obesity. GDF15 is synthesized as pro-GDF15, is dimerized, and is cleaved and secreted into the circulation as a mature dimer GDF15. Both the intracellular GDF15 and the circulating mature GDF15 are implicated in biological processes, such as energy homeostasis and body weight regulation. Although there have been many studies on GDF15, GFRAL, a member of the glial-derived neurotropic factor receptor α family, has only been recently identified as a receptor for mature GDF15. In this review, we focused on cancer and energy homeostasis along with obesity and body weight, and the effect of the identification of the GDF15 receptor in these investigations. In addition, the therapeutic potential of GDF15 as a pharmacological agent in obesity and other metabolic diseases was discussed.

Keywords: Aging; Appetite suppression; Cancer prevention; Energy metabolism; GFRAL receptor complex; Growth differentiation factor 15; Non-steroidal anti-inflammatory drug activated gene-1; Obesity; Survival.

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Conflict of interest statement

Conflict of interest statement: The authors declare no conflicts of interest.

Figures

Figure 1.
Figure 1.
Schematic diagram of various GDF15 proteins. GDF15 is synthesized in the cytoplasm with pro-GDF15 monomer, which then forms pro-GDF15 dimer. All the forms indicated are probably secreted into extracellular matrix, and, at least, mature GDF15 binds to receptor. The details are provided in the main text.
Figure 2.
Figure 2.
GDF15 translocation in the cells. GDF15 is translocated into the nucleus, and then, exported to cytoplasm. Finally, GDF15 is secreted into the extracellular matrix. CRM1 (green) participates in GDF15 translocation from nucleus to cytoplasm, whereas importin may participate in GDF15 translocation from cytoplasm to nucleus. Nuclear GDF15 may inhibit SMAD activity that regulates several genes associated with metastasis.
Figure 3.
Figure 3.
GDF15 effects on obesity. Some tissues express GDF15 and secrete mature GDF15 into the bloodstream. In the brain, mature GDF15 binds to GFRAL/RET receptor and controls food appetite via certain unknown kinase signaling. In addition, pro-GDF15 and mature GDF15 may affect several metabolic pathways, independent of GFRAL/RET receptor pathway. The details are provided in the main text.
See this image and copyright information in PMC

References

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