Clin Res Cardiol (2023). https://doi.org/10.1007/s00392-023-02180-w

Multifaceted effects of genetically caused thrombocytopenia on the development of the Metabolic Syndrome in mice

N. Burkhard1, J. Hoch1, D. Stallmann1, N. Schommer1, K. Krauel2, M. A. Hamad1, P. H. Mangin3, N. Gauchel1, D. Dürschmied2, N. Schanze2

1Cardiology and Angiology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg; 2Department of Cardiology, Angiology, Haemostaseology and Medical Intensive Care, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim; 3INSERM, Université de Strasbourg, Strasbourg, FR;

Background Metabolic Syndrome (MetS) refers to the co-occurrence of insulin resistance, hypertension, atherogenic dyslipidemia, and central obesity.1 On a molecular level, it is characterized by an aseptic inflammation in different tissues.2 MetS is a risk factor for the occurrence of cardiovascular, pancreatic, and liver diseases1 and is related to an increased overall mortality.3 Platelets are immune cells that initiate and accelerate many inflammatory processes.4 The chronic inflammation underlying the MetS is driven by different immune cells,5 but a specific role of platelets in this context has not yet been studied. Therefore, we investigated the influence of genetically caused thrombocytopenia on the development of the MetS in mice. Methods To investigate the influence of platelet abundance on the development of the MetS in mice, we used MPL-/- mice, with a knockout of the thrombopoietin-receptor-gene leading to constant thrombocytopenia and C57BL/6 J as control. Mice were fed a high-fat diet (HFD) or a chow diet (CD) for 19 weeks, starting at an age of 8 weeks. Weight measurements and blood collections from the tail vein were performed regularly. Metabolic caging (MC) was performed in week 15 and 16 of the diet feeding. To investigate glucose metabolism, glucose (GTT) and insulin tolerance test (ITT) were performed in week 17 and 18, respectively. At the end of the study, the immune cell composition in different organs was analyzed by flow-cytometry. Results Thrombocytopenia of the MPL-/- mice was confirmed by repeated blood analyses. Body weight gain and food intake were similar between the genotypes. Although MPL-/- mice showed less physical activity in MC and tend to be more insulin resistant, we could observe an improved glucose tolerance. Surprisingly, at the end of the study after 19 weeks of HFD, we detected higher levels of neutrophils in blood as well as higher proportions of proinflammatory Ly6Chigh monocytes, cytotoxic T-cells, and NKT cells in adipose tissue of MPL-/- mice. This was accompanied by a higher quantity of neutrophils and macrophages in bone marrow and spleen, suggesting a more pronounced inflammation in MPL-/- mice compared to WT. Conclusion In conclusion, thrombopoietin receptor deficiency has shown a protective effect on glucose metabolism, while conversely displaying a more inflammatory phenotype. References 1 Tariq, H., Nayudu, S., Akella, S., Glandt, M., and Chilimuri, S. (2016). Non-alcoholic fatty pancreatic disease: A review of literature. Gastroenterol. Res. 9, 87–91. 2 Nishimura, S., Manabe, I., & Nagai, R. (2009). Adipose tissue inflammation in obesity and metabolic syndrome. Discovery medicine, 8(41), 55–60. 3 Engin A. (2017). The Definition and Prevalence of Obesity and Metabolic Syndrome. Advances in experimental medicine and biology, 960, 1–17. 4 Duerschmied, D., Bode, C., & Ahrens, I. (2014). Immune functions of platelets. Thrombosis and haemostasis, 112(4), 678–691. 5 Talukdar, S., Oh, D. Y., Bandyopadhyay, G., Li, D., Xu, J., McNelis, J., Lu, M., Li, P., Yan, Q., Zhu, Y., Ofrecio, J., Lin, M., Brenner, M. B., & Olefsky, J. M. (2012). Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nature medicine, 18(9), 1407–1412.

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