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Nat Commun. 2017 Nov 23;8(1):1725. doi: 10.1038/s41467-017-01783-y.

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

Author information

1
Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Kraepelinstraße 2-10, 80804, Munich, Germany.
2
Institute of Diabetes and Obesity, Helmholtz Zentrum München, Parkring 13, 85748, Garching, Germany.
3
Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Kraepelinstraße 2-10, 80804, Munich, Germany.
4
Ludwig Maximilians University, Butenandtstr. 5-13, 81377, Munich, Germany.
5
Technical University Darmstadt, Institute of Organic Chemistry and Biochemistry, Alarich-Weiss-Str. 4, 64287, Darmstadt, Germany.
6
Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Kraepelinstraße 2-10, 80804, Munich, Germany. mschmidt@psych.mpg.de.

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.

PMID:
29170369
PMCID:
PMC5700978
DOI:
10.1038/s41467-017-01783-y
[Indexed for MEDLINE]
Free PMC Article

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