Summary: Researchers have identified a stress-associated protein that links the body’s stress-regulation system with metabolic control, revealing a potential new target for preventing or treating type 2 diabetes and metabolic dysfunction.
Source: Max Planck Institute.
Scientists at the Max Planck Institute of Psychiatry in Munich have shown, for the first time, that a stress-related protein present in muscle tissue can promote the development of diabetes. This discovery opens the possibility of an entirely new therapeutic approach.
Previous studies linked the protein FKBP51 to anxiety and depression because of its role in regulating the body’s stress response. When stress regulation is disrupted, mental health disorders can arise. The new research from the Max Planck Institute reveals an additional and surprising function: FKBP51 serves as a molecular bridge between stress signaling and metabolic regulation.
Project leader Mathias Schmidt explains that “FKBP51 influences a signaling cascade in muscle tissue that, under conditions of excessive calorie intake, leads to glucose intolerance — the hallmark of type 2 diabetes.” In other words, a high-fat or calorie-rich diet stresses the body metabolically, and increased FKBP51 levels in muscle reduce the tissue’s ability to absorb glucose. Over time, this impaired glucose uptake contributes to the development of obesity and diabetes.
Importantly, the researchers found that blocking FKBP51 prevents the onset of diabetes even when animals consume excessive calories or are exposed to stress. Lower levels of FKBP51 in skeletal muscle correlate with improved glucose tolerance and preserved metabolic function, indicating that modulating this protein can maintain normal glucose handling despite metabolic or environmental challenges.
Antagonist provides a novel treatment approach
Pharmacological compounds that antagonize FKBP51 were developed at the Max Planck Institute by Felix Hausch, now at the University of Darmstadt. In collaboration with researchers at the Technical University of Darmstadt and supported by regional funding, these antagonist compounds are being advanced toward clinical development. According to Alon Chen, Director at the Max Planck Institute of Psychiatry, “these findings could lead to completely new treatment approaches for diabetes and other metabolic diseases.”
The study demonstrates both genetic and pharmacological evidence: mice lacking the FKBP5 gene (encoding FKBP51) are protected from weight gain induced by a high-fat diet, show improved glucose tolerance and enhanced insulin signaling in skeletal muscle. Chronic treatment with a selective FKBP51 antagonist reproduces the benefits seen in the knockout animals, improving body weight regulation and glucose tolerance. Notably, short-term treatment improves glucose tolerance before any reduction in body weight is observed, suggesting direct effects on glucose handling independent of weight loss.
Mechanistically, the researchers identified a previously unknown interaction between FKBP51 and AS160, a substrate of AKT2 that plays a central role in glucose uptake. FKBP51 antagonism increases phosphorylation of AS160, promotes the translocation of the glucose transporter GLUT4 to the plasma membrane, and thereby enhances glucose uptake in skeletal muscle cells. These molecular events explain how FKBP51 links stress signaling and energy homeostasis and support the idea that targeting FKBP51 could break the connection between stress and metabolic disease.
Source: Max Planck Institute
Publisher: NeuroscienceNews.com (organized coverage)
Image source: Public domain image credited to NeuroscienceNews.com
Original research: “Stress-responsive FKBP51 regulates AKT2-AS160 signaling and metabolic function” — published in Nature Communications. doi:10.1038/s41467-017-01783-y
Abstract
Stress-responsive FKBP51 regulates AKT2-AS160 signaling and metabolic function
FKBP51 (encoded by FKBP5) is a stress-responsive co-chaperone that modulates stress reactivity, and genetic variants of FKBP5 have been associated with traits related to type 2 diabetes (T2D) and other stress-related disorders. This study demonstrates that FKBP51 also influences energy balance and glucose homeostasis. FKBP5 knockout mice were protected from high-fat diet–induced weight gain, exhibited improved glucose tolerance, and showed increased insulin signaling in skeletal muscle. Chronic administration of a novel FKBP51 antagonist, SAFit2, mimicked the metabolic benefits of FKBP51 deletion, improving both body weight control and glucose tolerance. Shorter SAFit2 treatment revealed that glucose tolerance improvements occur before weight loss, indicating a direct effect on glucose metabolism. Mechanistically, FKBP51 associates with AS160 (a downstream substrate of AKT2 that regulates glucose uptake). Antagonizing FKBP51 enhances AS160 phosphorylation, increases GLUT4 presence at the plasma membrane, and boosts glucose uptake in skeletal myotubes. The results identify FKBP51 as a mediator that links stress responses to the development of T2D and highlight FKBP51 as a promising therapeutic target for metabolic disease.
Study citation: 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 & Mathias V. Schmidt. Published online November 23, 2017.