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Georgiadi, A. ; Lopez Salazar, V. ; El-Merahbi, R. ; Karikari, R.A. ; Ma, X.* ; Mourao, A. ; Klepac, K. ; Bühler, L. ; Alfaro, A.J. ; Kaczmarek, I.* ; Linford, A. ; Bosma, M.* ; Shilkova, O.* ; Ritvos, O.* ; Nakamura, N.* ; Hirose, S.* ; Lassi, M. ; Teperino, R. ; Machado, J. ; Scheideler, M. ; Dietrich, A.* ; Geerlof, A. ; Feuchtinger, A. ; Blutke, A. ; Fischer, K. ; Müller, T.D. ; Kessler, K.* ; Schöneberg, T.* ; Thor, D.* ; Hornemann, S.* ; Kruse, M.* ; Nawroth, P.P. ; Pivovarova-Ramich, O.* ; Pfeiffer, A.F.H.* ; Sattler, M. ; Blüher, M.* ; Herzig, S.

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

Nat. Commun. 12:2999 (2021)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Glut4 Translocation; Protein; Fat; Resistance; Obesity; 3t3-l1; Mouse; Expression; Receptors; Cells
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Zeitschrift Nature Communications
Quellenangaben Band: 12, Heft: 1, Seiten: , Artikelnummer: 2999 Supplement: ,
Verlag Nature Publishing Group
Verlagsort London
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Cancer (IDC)
Institute of Structural Biology (STB)
Institute of Experimental Genetics (IEG)
Research Unit Analytical Pathology (AAP)
Institute of Diabetes and Obesity (IDO)
Förderungen EFSD grant
The Rubicon Netherlands Organization for Scientific research (NWO)-mobility grant
German Federal Ministry of Education and Research (BMBF)
DFG
Helmholtz Association
Karolinska Institute derived funds
Deutsche Forschungsgemeinschaft, Obesity Mechanisms