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GDF15: emerging biology and therapeutic applications for obesity and cardiometabolic disease

Nature Reviews Endocrinology volume 17, pages 592–607 (2021)Cite this article

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Abstract

Growth differentiation factor 15 (GDF15) is a member of the TGFβ superfamily whose expression is increased in response to cellular stress and disease as well as by metformin. Elevations in GDF15 reduce food intake and body mass in animal models through binding to glial cell-derived neurotrophic factor family receptor alpha-like (GFRAL) and the recruitment of the receptor tyrosine kinase RET in the hindbrain. This effect is largely independent of other appetite-regulating hormones (for example, leptin, ghrelin or glucagon-like peptide 1). Consistent with an important role for the GDF15–GFRAL signalling axis, some human genetic studies support an interrelationship with human obesity. Furthermore, findings in both mice and humans have shown that metformin and exercise increase circulating levels of GDF15. GDF15 might also exert anti-inflammatory effects through mechanisms that are not fully understood. These unique and distinct mechanisms for suppressing food intake and inflammation makes GDF15 an appealing candidate to treat many metabolic diseases, including obesity, type 2 diabetes mellitus, non-alcoholic fatty liver disease, cardiovascular disease and cancer cachexia. Here, we review the mechanisms regulating GDF15 production and secretion, GDF15 signalling in different cell types, and how GDF15-targeted pharmaceutical approaches might be effective in the treatment of metabolic diseases.

Key points

  • Growth differentiation factor 15 (GDF15) is expressed in multiple cell types and can be increased by cellular stressors, including hypoxia, mitochondrial dysfunction, metformin and endurance exercise.

  • Increases in GDF15 secretion are mediated through mitochondrial stress and by activation of the integrated stress response pathway as well as, potentially, via AMPK.

  • GDF15 reduces the intake of high-fat diets in animal models through binding to glial cell-derived neurotrophic factor family receptor alpha-like (GFRAL) and the recruitment of the receptor tyrosine kinase RET in the hindbrain and this event is required for weight loss and improved glycaemic control.

  • Evidence suggests that GDF15 might alleviate non-alcoholic fatty liver disease and non-alcoholic steatohepatitis but the mechanisms mediating the anti-inflammatory effects and whether these are independent of reductions in body weight remain to be determined.

  • GDF15 might have cardioprotective effects by reducing atherosclerosis, cardiac hypertrophy and ischaemia–reperfusion injury; however, the mechanisms mediating these effects are still unclear.

  • Clinical testing of long-acting analogues of GDF15 is under way and will be important to determine whether the beneficial effects observed in animal models are translated to humans in a safe and efficacious manner.

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Fig. 1: GDF15 regulation, maturation and secretion.
Fig. 2: A model of the formation of the GDF15–GFRAL–RET signalling complex.
Fig. 3: Proposed mechanisms by which GDF15 suppresses energy intake and obesity.
Fig. 4: Potential effects of GDF15 in cardiometabolic diseases beyond obesity.

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Acknowledgements

G.R.S. acknowledges the support of a Diabetes Canada Investigator Award (DI-5-17-5302-GS), a Canadian Institutes of Health Research Foundation Grant (201709FDN-CEBA-116200), a Tier 1 Canada Research Chair in Metabolic Diseases and a J. Bruce Duncan Endowed Chair in Metabolic Diseases. L.K.T. acknowledges the support of a CIHR Post-Doctoral Fellowship Award and Michael DeGroote Fellowship Award in Basic Biomedical Science.

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Authors and Affiliations

  1. Centre for Metabolism, Obesity and Diabetes Research and the Department of Medicine, McMaster University, Hamilton, ON, Canada

    Dongdong Wang, Emily A. Day, Logan K. Townsend & Gregory R. Steinberg

  2. Global Obesity and Liver Disease Research, Novo Nordisk A/S, Maaloev, Denmark

    Djordje Djordjevic & Sebastian Beck Jørgensen

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  1. Dongdong Wang
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Contributions

D.W. researched data for the article. All authors made substantial contributions to the discussion of content, wrote the article, and reviewed and/or edited the manuscript before submission.

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Correspondence to Gregory R. Steinberg.

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Competing interests

D.D. and S.B.J. are employees of Novo Nordisk A/S, a pharmaceutical company producing and selling medicine for the treatment of diabetes and obesity. G.R.S. is a co-founder and shareholder of Espervita Therapeutics, a company developing new medications for liver cancer. McMaster University has received funding from Espervita Therapeutics, Esperion Therapeutics, Poxel Pharmaceuticals and Novo Nordisk for research conducted in the laboratory of G.R.S. G.R.S. has received consulting/speaking fees from Astra Zeneca, Eli Lilly, Esperion Therapeutics, Merck, Poxel Pharmaceuticals and Takeda. The other authors declare no competing interests.

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Common Metabolic Diseases Knowledge Portal: https://t2d.hugeamp.org/region.html?chr=19&end=18549986&phenotype=WHRadjBMI&start=18435541

The Blood Atlas: https://www.proteinatlas.org/humanproteome/blood

the Human Protein Atlas GFRAL expression: https://www.proteinatlas.org/ENSG00000187871-GFRAL/blood

Glossary

Non-alcoholic fatty liver disease

(NAFLD). A spectrum of liver pathology ranging from liver steatosis (>5% lipids) to inflammation and fibrosis, known as non-alcoholic steatohepatitis, that is an important risk factor for type 2 diabetes mellitus, cardiovascular disease, liver cirrhosis and hepatocellular carcinoma.

Integrated stress response

A eukaryotic cellular stress response to restore cellular homeostasis by phosphorylation of eIF2 by four specialized kinases (PERK, GCN2, PKR and HRI), leading to a decrease in global protein synthesis and an increase in the expression of specific genes, including ATF4.

Mitochondrial unfolded protein response

(UPR). This cellular stress response is triggered when unfolded or misfolded proteins accumulate in mitochondria beyond the protective capacity of chaperone proteins.

Cancer cachexia

This state is characterized by reductions in appetite and increases in energy expenditure, which leads to involuntary loss of adipose and lean mass that is associated with poor quality of life and reduced survival.

Foam cells

Macrophages or vascular smooth muscle cells with a foamy appearance, which are over-laden with lipids and are a key cell type contributing to the development of atherosclerotic cardiovascular disease (coronary artery disease).

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Wang, D., Day, E.A., Townsend, L.K. et al. GDF15: emerging biology and therapeutic applications for obesity and cardiometabolic disease. Nat Rev Endocrinol 17, 592–607 (2021). https://doi.org/10.1038/s41574-021-00529-7

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