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

Georgia Balsevich (), Alexander S. Häusl, Carola W. Meyer, Stoyo Karamihalev, Xixi Feng, Max L. Pöhlmann, Carine Dournes, Andres Uribe-Marino, Sara Santarelli, Christiana Labermaier, Kathrin Hafner, Tianqi Mao, Michaela Breitsamer, Marily Theodoropoulou, Christian Namendorf, Manfred Uhr, Marcelo Paez-Pereda, Gerhard Winter, Felix Hausch, Alon Chen, Matthias H. Tschöp, Theo Rein, Nils C. Gassen and Mathias V. Schmidt ()
Additional contact information
Georgia Balsevich: Max Planck Institute of Psychiatry
Alexander S. Häusl: Max Planck Institute of Psychiatry
Carola W. Meyer: Helmholtz Zentrum München
Stoyo Karamihalev: Max Planck Institute of Psychiatry
Xixi Feng: Max Planck Institute of Psychiatry
Max L. Pöhlmann: Max Planck Institute of Psychiatry
Carine Dournes: Max Planck Institute of Psychiatry
Andres Uribe-Marino: Max Planck Institute of Psychiatry
Sara Santarelli: Max Planck Institute of Psychiatry
Christiana Labermaier: Max Planck Institute of Psychiatry
Kathrin Hafner: Max Planck Institute of Psychiatry
Tianqi Mao: Max Planck Institute of Psychiatry
Michaela Breitsamer: Ludwig Maximilians University
Marily Theodoropoulou: Max Planck Institute of Psychiatry
Christian Namendorf: Max Planck Institute of Psychiatry
Manfred Uhr: Max Planck Institute of Psychiatry
Marcelo Paez-Pereda: Max Planck Institute of Psychiatry
Gerhard Winter: Ludwig Maximilians University
Felix Hausch: Institute of Organic Chemistry and Biochemistry
Alon Chen: Max Planck Institute of Psychiatry
Matthias H. Tschöp: Helmholtz Zentrum München
Theo Rein: Max Planck Institute of Psychiatry
Nils C. Gassen: Max Planck Institute of Psychiatry
Mathias V. Schmidt: Max Planck Institute of Psychiatry

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/s41467-017-01783-y

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