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

Georgia Balsevich,Carola W Meyer,Max L Pöhlmann,Alexander S Häusl,Matthias H Tschöp,Alon Chen,Theo Rein,Nils C Gassen,Kathrin Hafner,Xiangyu Feng ,Manfred Uhr,Michaela Breitsamer,Stoyo Karamihalev,Christian Namendorf,Christiana Labermaier,Carine Dournes,Sara Santarelli,Marily Theodoropoulou,Gerhard Winter,Marcelo Páez-Pereda ,Felix Hausch,Tianqi Mao,A Uribe-Mariño ,Mathias Schmidt

doi:10.1038/s41467-017-01783-y

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.

Highlights

The co-chaperone FKBP5 is a stress-responsive protein-regulating stress reactivity, and its genetic variants are associated with type 2 diabetes (T2D) related traits and other stress-related disorders
We found that 51KO mice fed with a standard chow diet showed a modest body weight reduction, reduced adiposity, and increased lean mass compared to WT littermates (Fig. 1a)
This is in line with earlier preclinical and human studies, which identified an association between FK506-binding protein 51 (FKBP51) ablation and FKBP5 Singlenucleotide polymorphisms (SNPs) on traits related to body weight regulation and T2D, respectively[14, 15]

Summary

Introduction

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. Fkbp[5] knockout (51KO) mice are protected from high-fat diet-induced weight gain, show improved glucose tolerance and increased insulin signaling in skeletal muscle. Preclinical studies in animal models have demonstrated that complete loss of FKBP51 protects against HFD-induced body weight gain and hepatic steatosis, which is, in part, explained by an increased expression of uncoupling protein 1 (UCP1), a specific marker of browning, in white adipose tissue (WAT) and increased thermogenesis[15]. AKT is a central node within the insulin signaling pathway, and deregulation of AKT activation, most notably AKT2 activation, has been linked to the pathogenesis of diabetes and obesity[17, 18] In this context, FKBP51 may be an important regulator of insulin signaling and energy and glucose homeostasis[19]. We aimed to characterize the role of FKBP51 in energy and glucose homeostasis using a combination of Fkbp[5] knockout (51KO) mice, Initial body weight (g) a

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Results

Conclusion