TY - JOUR
T1 - Orphan GPR116 mediates the insulin sensitizing effects of the hepatokine FNDC4 in adipose tissue
AU - Georgiadi, Anastasia
AU - Lopez-Salazar, Valeria
AU - Merahbi, Rabih El
AU - Karikari, Rhoda Anane
AU - Ma, Xiaochuan
AU - Mourão, André
AU - Klepac, Katarina
AU - Bühler, Lea
AU - Alfaro, Ana Jimena
AU - Kaczmarek, Isabell
AU - Linford, Adam
AU - Bosma, Madeleen
AU - Shilkova, Olga
AU - Ritvos, Olli
AU - Nakamura, Nobuhiro
AU - Hirose, Shigehisa
AU - Lassi, Maximilian
AU - Teperino, Raffaele
AU - Machado, Juliano
AU - Scheideler, Marcel
AU - Dietrich, Arne
AU - Geerlof, Arie
AU - Feuchtinger, Annette
AU - Blutke, Andreas
AU - Fischer, Katrin
AU - Müller, Timo Dirk
AU - Kessler, Katharina
AU - Schöneberg, Torsten
AU - Thor, Doreen
AU - Hornemann, Silke
AU - Kruse, Michael
AU - Nawroth, Peter
AU - Pivovarova-Ramich, Olga
AU - Pfeiffer, Andreas Friedrich Hermann
AU - Sattler, Michael
AU - Blüher, Matthias
AU - Herzig, Stephan
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85106293489
U2 - 10.1038/s41467-021-22579-1
DO - 10.1038/s41467-021-22579-1
M3 - Article
C2 - 34016966
AN - SCOPUS:85106293489
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2999
ER -
SDG 3 Good Health and Well-being