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Balsevich, G.* ; Häusl, A.S.* ; Meyer, C.W. ; Karamihalev, S.* ; Feng, X.* ; Pöhlmann, M.L.* ; Dournes, C.* ; Uribe-Marino, A.* ; Santarelli, S.* ; Labermaier, C.* ; Hafner, K.* ; Mao, T.* ; Breitsamer, M.* ; Theodoropoulou, M.* ; Namendorf, C.* ; Uhr, M.* ; Paez-Pereda, M.* ; Winter, G.* ; Hausch, F.* ; Chen, A.* ; Tschöp, M.H. ; Rein, T.* ; Gassen, N.C.* ; Schmidt, M.V.*

Stress-responsive FKBP51 regulates AKT2-AS160 signaling and metabolic function.

Nat. Commun. 8:1725 (2017)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
The co-chaperone FKBP5 is a stress-responsive protein-regulating stress reactivity, and its genetic variants are associated with T2D related traits and other stress-related disorders. Here we show that FKBP51 plays a role in energy and glucose homeostasis. Fkbp5 knockout (51KO) mice are protected from high-fat diet-induced weight gain, show improved glucose tolerance and increased insulin signaling in skeletal muscle. Chronic treatment with a novel FKBP51 antagonist, SAFit2, recapitulates the effects of FKBP51 deletion on both body weight regulation and glucose tolerance. Using shorter SAFit2 treatment, we show that glucose tolerance improvement precedes the reduction in body weight. Mechanistically, we identify a novel association between FKBP51 and AS160, a substrate of AKT2 that is involved in glucose uptake. FKBP51 antagonism increases the phosphorylation of AS160, increases glucose transporter 4 expression at the plasma membrane, and ultimately enhances glucose uptake in skeletal myotubes. We propose FKBP51 as a mediator between stress and T2D development, and potential target for therapeutic approaches.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Diet-induced Obesity; Skeletal-muscle; Glucocorticoid-receptor; Glut4 Translocation; Immunophilin Fkbp51; Insulin-resistance; Diabetes-mellitus; Gene-expression; Adipose-tissue; Mice Lacking
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Zeitschrift Nature Communications
Quellenangaben Band: 8, Heft: 1, Seiten: , Artikelnummer: 1725 Supplement: ,
Verlag Nature Publishing Group
Verlagsort London
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes and Obesity (IDO)