Orphan GPR116 mediates the insulin sensitizing effects of the hepatokine FNDC4 in adipose tissue.
英文:
Orphan GPR116 mediates the insulin sensitizing effects of the hepatokine FNDC4 in adipose tissue.
著者
和文:
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,
中村 信大,
広瀬 茂久,
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,
Stephan Herzig.
英文:
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,
Stephan Herzig.
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.
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