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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
Schlagwörter Glut4 Translocation; Protein; Fat; Resistance; Obesity; 3t3-l1; Mouse; Expression; Receptors; Cells
Sprache englisch
Veröffentlichungsjahr 2021
HGF-Berichtsjahr 2021
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
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Cancer (IDC)
Institute of Structural Biology (STB)
Institute of Experimental Genetics (IEG)
CF Pathology & Tissue Analytics (CF-PTA)
Research Unit Analytical Pathology (AAP)
Institute of Diabetes and Obesity (IDO)
POF Topic(s) 90000 - German Center for Diabetes Research
30203 - Molecular Targets and Therapies
30505 - New Technologies for Biomedical Discoveries
30205 - Bioengineering and Digital Health
30201 - Metabolic Health
Forschungsfeld(er) Helmholtz Diabetes Center
Enabling and Novel Technologies
Genetics and Epidemiology
PSP-Element(e) G-501900-252
G-501900-251
G-503000-001
G-501900-069
G-501900-253
A-630600-001
G-500390-001
G-500600-001
G-502200-001
G-501900-221
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
DOI 10.1038/s41467-021-22579-1
WOS ID WOS:000658758500001
Scopus ID 85106293489
PubMed ID 34016966
Erfassungsdatum 2021-06-16
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