Orphan GPR116 mediates the insulin sensitizing effects of the hepatokine FNDC4 in adipose tissue

Anastasia Georgiadi (), Valeria Lopez-Salazar, Rabih El- Merahbi, Rhoda Anane Karikari, Xiaochuan Ma, André Mourão, Katarina Klepac, Lea Bühler, Ana Jimena Alfaro, Isabell Kaczmarek, Adam Linford, Madeleen Bosma, Olga Shilkova, Olli Ritvos, Nobuhiro Nakamura, Shigehisa Hirose, Maximilian Lassi, Raffaele Teperino, Juliano Machado, Marcel Scheideler, Arne Dietrich, Arie Geerlof, Annette Feuchtinger, Andreas Blutke, Katrin Fischer, Timo Dirk Müller, Katharina Kessler, Torsten Schöneberg, Doreen Thor, Silke Hornemann, Michael Kruse, Peter Nawroth, Olga Pivovarova-Ramich, Andreas Friedrich Hermann Pfeiffer, Michael Sattler, Matthias Blüher and Stephan Herzig ()
Additional contact information
Anastasia Georgiadi: German Research Center for Environmental Health
Valeria Lopez-Salazar: German Research Center for Environmental Health
Rabih El- Merahbi: German Research Center for Environmental Health
Rhoda Anane Karikari: German Research Center for Environmental Health
Xiaochuan Ma: Karolinska Institute
André Mourão: German Research Center for Environmental Health
Katarina Klepac: German Research Center for Environmental Health
Lea Bühler: German Research Center for Environmental Health
Ana Jimena Alfaro: German Research Center for Environmental Health
Isabell Kaczmarek: University of Leipzig
Adam Linford: German Research Center for Environmental Health
Madeleen Bosma: Karolinska Institute
Olga Shilkova: Karolinska Institute
Olli Ritvos: University of Helsinki
Nobuhiro Nakamura: Tokyo Institute of Technology
Shigehisa Hirose: Tokyo Institute of Technology
Maximilian Lassi: German Center for Diabetes Research (DZD)
Raffaele Teperino: German Center for Diabetes Research (DZD)
Juliano Machado: German Research Center for Environmental Health
Marcel Scheideler: German Research Center for Environmental Health
Arne Dietrich: University of Leipzig
Arie Geerlof: German Research Center for Environmental Health
Annette Feuchtinger: German Research Center for Environmental Health
Andreas Blutke: German Research Center for Environmental Health
Katrin Fischer: German Research Center for Environmental Health
Timo Dirk Müller: German Research Center for Environmental Health
Katharina Kessler: German Center for Diabetes Research (DZD)
Torsten Schöneberg: University of Leipzig
Doreen Thor: University of Leipzig
Silke Hornemann: German Center for Diabetes Research (DZD)
Michael Kruse: German Institute of Human Nutrition Potsdam-Rehbruecke
Peter Nawroth: German Research Center for Environmental Health
Olga Pivovarova-Ramich: German Center for Diabetes Research (DZD)
Andreas Friedrich Hermann Pfeiffer: German Center for Diabetes Research (DZD)
Michael Sattler: German Research Center for Environmental Health
Matthias Blüher: University of Leipzig
Stephan Herzig: German Research Center for Environmental Health

Nature Communications, 2021, vol. 12, issue 1, 1-21

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-22579-1

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