Anastasia Georgiadi1,2,3,4,5, Valeria Lopez-Salazar6,7,8,9, Rabih El- Merahbi6,7,8,9, Rhoda Anane Karikari6,7,8,9, Xiaochuan Ma10, André Mourão11, Katarina Klepac6,7,8,9, Lea Bühler6,7,8,9, Ana Jimena Alfaro6,7,8,9, Isabell Kaczmarek12, Adam Linford6,7,8,9, Madeleen Bosma10, Olga Shilkova10, Olli Ritvos13, Nobuhiro Nakamura14, Shigehisa Hirose14, Maximilian Lassi9,15, Raffaele Teperino9,15, Juliano Machado6,7,8,9, Marcel Scheideler6,7,8,9, Arne Dietrich16, Arie Geerlof11, Annette Feuchtinger17, Andreas Blutke17, Katrin Fischer18, Timo Dirk Müller18, Katharina Kessler9,19,20,21, Torsten Schöneberg12, Doreen Thor12, Silke Hornemann9,19, Michael Kruse19,20, Peter Nawroth6,7,9, Olga Pivovarova-Ramich9,19,20,22, Andreas Friedrich Hermann Pfeiffer9,19,20, Michael Sattler11, Matthias Blüher23, Stephan Herzig24,25,26,27. 1. Institute for Diabetes and Cancer, Helmholtz Diabetes Center, Helmholtz Centre Munich, German Research Center for Environmental Health, Neuherberg, Germany. anastasia.georgiadi@helmholtz-muenchen.de. 2. Joint Heidelberg-IDC Transnational Diabetes Program, Heidelberg University Hospital, Heidelberg, Germany. anastasia.georgiadi@helmholtz-muenchen.de. 3. Chair Molecular Metabolic Control, Medical Faculty, Technical University Munich, Munich, Germany. anastasia.georgiadi@helmholtz-muenchen.de. 4. German Center for Diabetes Research (DZD), Neuherberg, Germany. anastasia.georgiadi@helmholtz-muenchen.de. 5. Department for Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden. anastasia.georgiadi@helmholtz-muenchen.de. 6. Institute for Diabetes and Cancer, Helmholtz Diabetes Center, Helmholtz Centre Munich, German Research Center for Environmental Health, Neuherberg, Germany. 7. Joint Heidelberg-IDC Transnational Diabetes Program, Heidelberg University Hospital, Heidelberg, Germany. 8. Chair Molecular Metabolic Control, Medical Faculty, Technical University Munich, Munich, Germany. 9. German Center for Diabetes Research (DZD), Neuherberg, Germany. 10. Department for Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden. 11. Institute of Structural Biology, Helmholtz Centre Munich, German Research Center for Environmental Health, Neuherberg, Germany. 12. Rudolf-Schönheimer-Institute for Biochemistry, Faculty of Medicine, University of Leipzig, Leipzig, Germany. 13. Biomedicum Helsinki and Department of Bacteriology, Haartman Institute, University of Helsinki, Helsinki, Finland. 14. Department of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Japan. 15. Institute of Experimental Genetics, Helmholtz Diabetes Center, Helmholtz Centre Munich, German Research Center for Environmental Health, Neuherberg, Germany. 16. Department of Surgery, University of Leipzig, Leipzig, Germany. 17. Core Facility Pathology & Tissue Analytics Research Unit Analytical Pathology, Helmholtz Centre Munich, German Research Center for Environmental Health, Neuherberg, Germany. 18. Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Centre Munich, German Research Center for Environmental Health, Neuherberg, Germany. 19. Department of Clinical Nutrition, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. 20. Department of Endocrinology, Diabetes and Nutrition, Campus Benjamin Franklin, Charité University of Medicine, Berlin, Germany. 21. Biomineral Research Group, Department of Veterinary Medicine, University of Cambridge, Cambridge, UK. 22. Research Group Molecular Nutritional Medicine, Department of Molecular Toxicology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany. 23. Department of Medicine, University of Leipzig, Leipzig, Germany. 24. Institute for Diabetes and Cancer, Helmholtz Diabetes Center, Helmholtz Centre Munich, German Research Center for Environmental Health, Neuherberg, Germany. stephan.herzig@helmholtz-muenchen.de. 25. Joint Heidelberg-IDC Transnational Diabetes Program, Heidelberg University Hospital, Heidelberg, Germany. stephan.herzig@helmholtz-muenchen.de. 26. Chair Molecular Metabolic Control, Medical Faculty, Technical University Munich, Munich, Germany. stephan.herzig@helmholtz-muenchen.de. 27. German Center for Diabetes Research (DZD), Neuherberg, Germany. stephan.herzig@helmholtz-muenchen.de.
Abstract
The proper functional interaction between different tissues represents a key component in systemic metabolic control. Indeed, disruption of endocrine inter-tissue communication is a hallmark of severe metabolic dysfunction in obesity and diabetes. Here, we show that the FNDC4-GPR116, liver-white adipose tissue endocrine axis controls glucose homeostasis. We found that the liver primarily controlled the circulating levels of soluble FNDC4 (sFNDC4) and lowering of the hepatokine FNDC4 led to prediabetes in mice. Further, we identified the orphan adhesion GPCR GPR116 as a receptor of sFNDC4 in the white adipose tissue. Upon direct and high affinity binding of sFNDC4 to GPR116, sFNDC4 promoted insulin signaling and insulin-mediated glucose uptake in white adipocytes. Indeed, supplementation with FcsFNDC4 in prediabetic mice improved glucose tolerance and inflammatory markers in a white-adipocyte selective and GPR116-dependent manner. Of note, the sFNDC4-GPR116, liver-adipose tissue axis was dampened in (pre) diabetic human patients. Thus our findings will now allow for harnessing this endocrine circuit for alternative therapeutic strategies in obesity-related pre-diabetes.
The proper functional interaction between different tissues represents a key component in systemic metabolic control. Indeed, disruption of endocrine inter-tissue communin class="Chemical">pan class="Gene">catn>ion is a hallmark of severe pan>n class="Disease">metabolic dysfunction in obesity and diabetes. Here, we show that the FNDC4-GPR116, liver-white adipose tissue endocrine axis controls glucose homeostasis. We found that the liver primarily controlled the circulating levels of soluble FNDC4 (sFNDC4) and lowering of the hepatokine FNDC4 led to prediabetes in mice. Further, we identified the orphan adhesion GPCRGPR116 as a receptor of sFNDC4 in the white adipose tissue. Upon direct and high affinity binding of sFNDC4 to GPR116, sFNDC4 promoted insulin signaling and insulin-mediated glucose uptake in white adipocytes. Indeed, supplementation with FcsFNDC4 in prediabeticmice improved glucose tolerance and inflammatory markers in a white-adipocyte selective and GPR116-dependent manner. Of note, the sFNDC4-GPR116, liver-adipose tissue axis was dampened in (pre) diabetichumanpatients. Thus our findings will now allow for harnessing this endocrine circuit for alternative therapeutic strategies in obesity-related pre-diabetes.
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