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Revisiting the role of GDF15 in atherosclerosis in mouse and human

Acta Pharmacologica Sinica volume 46, pages 2663–2676 (2025)Cite this article

Abstract

Growth differentiation factor 15 (GDF15) is a key regulator of food intake and energy metabolism. GDF15 mimetic drugs for the treatment of metabolic syndrome and obesity are under clinical development. While GDF15 presents a promising target for weight management, its potential cardiovascular actions remain elusive. In this study we investigated the role of GDF15 in macrophage function and atherosclerosis pathogenesis and whether GDF15 acts both as a biomarker and mediator of atherosclerosis severity. ApoE−/− mice were fed a high-cholesterol diet (HCD, 1.25% cholesterol) for 6, 12 or 18 weeks to establish atherosclerotic models. We showed that serum levels of GDF15 were elevated in ApoE−/− mice with atheroprogression; increased serum levels of GDF15 were also observed in patients with coronary artery disease. Enlightened by this finding, we established atherosclerotic model in Gdf15−/− mice by injecting with AAV8-PCSK9D377Y virus and feeding HCD for 12 or 16 weeks. We showed that global Gdf15 knockout, whether in male or female mice, did not alter plaque size in en face aorta, lesion in aortic sinus, size of necrotic core or plaque composition. In macrophage-derived foam cells isolated from atherosclerotic mice, neither Gdf15 deletion nor the treatment with recombinant GDF15 protein (1, 10, 100 ng/mL) affected lipid deposition or macrophage polarization. To translate this finding into a clinically relevant scenario, we performed Mendelian randomization (MR) analysis, and found no significant causal association between circulating GDF15 levels and the incidence of cardiovascular diseases. Furthermore, MR studies suggest that genetic associations between GDF15 and factors such as BMI, ApoB, LDL and HDL were not significant in plasma data from the UK Biobank and the deCODE cohort. In summary, this study demonstrates that global Gdf15 deficiency does not affect the development of atherosclerosis in male or female mice despite the positive association between circulating GDF15 levels and disease progression in mice and human. Thus, GDF15 in circulation is a potential biomarker, but not a causal mediator, of atherosclerosis. Long-term cardiovascular safety of GDF15-targeted therapies warrants further investigation.

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Fig. 1: GDF15 levels are elevated in mouse and human atherosclerosis.
Fig. 2: Global knockout of Gdf15 does not alter the size of atherosclerotic lesion nor plaque composition in male mice.
Fig. 3: Global knockout of Gdf15 does not alter the size of atherosclerotic lesion nor plaque composition in female mice.
Fig. 4: Deficiency of Gdf15 does not alter lipid accumulation or polarization in macrophages isolated from male atherosclerotic mice.
Fig. 5: Deficiency of Gdf15 does not alter lipid accumulation or polarization in macrophages isolated from female atherosclerotic mice.
Fig. 6: GDF15 levels and cardiovascular diseases in human.

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Acknowledgements

This study was supported by National Natural Science Foundation of China (82370444, 12411530127). This work was also supported by the Program for Innovative Research Team of  the First Affiliated Hospital of USTC (CXGG02), Anhui Provincial Natural Science Foundation (2208085J08) and USTC Research Funds of the Double First-Class Initiative (YD9110002089) and the Research Funds of Centre for Leading Medicine and Advanced Technologies of IHM.

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  1. These authors contributed equally: Mo-nan Liu, Zheng-hong Liu, Rui-xue Leng

Authors and Affiliations

  1. Department of Endocrinology, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China

    Mo-nan Liu, Zheng-hong Liu, Jian-ping Weng & Suo-wen Xu

  2. Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, 230032, China

    Rui-xue Leng

  3. Centre for Cardio-metabolic Research in Africa, Division of Medical Physiology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa

    Hans Strijdom

  4. Anhui Provincial Key Laboratory of Metabolic Health and Panvascular Diseases, Hefei, 230001, China

    Jian-ping Weng & Suo-wen Xu

  5. Institute of Endocrine and Metabolic Diseases, University of Science and Technology of China, Hefei, 230001, China

    Jian-ping Weng & Suo-wen Xu

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SWX conceptualized the project. MNL, ZHL and RXL performed the experiments, generated and analyzed the data. HS and JPW provided conceptual inputs and suggestions into the manuscript. All authors edited and approved the manuscript.

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Liu, Mn., Liu, Zh., Leng, Rx. et al. Revisiting the role of GDF15 in atherosclerosis in mouse and human. Acta Pharmacol Sin 46, 2663–2676 (2025). https://doi.org/10.1038/s41401-025-01561-3

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  • DOI: https://doi.org/10.1038/s41401-025-01561-3

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