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

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.

Elucidation of the FKBP25-60S Ribosomal Protein L7a Stress Response Signaling During Ischemic Injury

“…Stress-responsive FKBP51 regulates AKT2-AS160 signaling and metabolic function [33]. Notably, the localization and intensity of FKBP12 increased in the cytosol and decreased in the nucleus until 24 h after reperfusion in hippocampus CA1 neurons [34].…”

The selective FKBP51 inhibitor SAFit2 reduces alcohol consumption and reinstatement of conditioned alcohol effects in mice

“…Bottles were changed and weighed daily. The consumed amount of alcohol and water relative to body weight and the preference vs water were measured …”

“…The system automatically recorded the number of entries made, the time spent, and distance moved in each compartment for each trial. An unbiased design was used, ie, half the mice were conditioned to their preferred compartment and half to their nonpreferred compartment . Animals were injected (ip) immediately before each trial with either saline or 2 g/kg alcohol (ip), a dose which has no sedative effects and which was previously shown to have efficient reinforcing effects in WT mice .…”

Post-translational modifications and stress adaptation: the paradigm of FKBP51

“…Mechanistically, this effect appears to be achieved through the differential association of FKBP51 and its close homolog FKBP52 with CDK5 and its regulatory protein p35 [69]. Metabolic function is impacted by FKBP51 through protein associations that dephosphorylate and thus inhibit Akt2, leading to dephosphorylation and thus inhibition of AS160 and reduced glucose uptake [70].…”