The stress-responsive psychiatric risk factor FKBP51 as a novel central regulator of metabolic (dys)function

• Applicants: Dr. Nils Gassen; Privatdozent Dr. Mathias V. Schmidt, Ph.D.
• Subject Area: Biological Psychiatry ; Molecular and Cellular Neurology and Neuropathology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 453645443

Homeostatic mechanisms govern the stress response, energy balance, and glucose homeostasis in order to maintain a dynamic equilibrium following internal or external challenges. This requires a complex physiological response (involving multiple organ systems) to sense, integrate, and respond to changes in the environment. Interestingly, regulation of these homeostatic systems relies on many shared environmental and genetic factors, whereby manipulation of one factor can simultaneously influence stress-coping behaviours, body weight, and blood glucose. Identification of such shared factors may prove beneficial in treating stress-related comorbidities such as psychiatric disorders, obesity, and diabetes. In this context, FK506 binding protein 51 (FKBP51) has recently been identified as a promising therapeutic target for stress-related psychiatric disorders and obesity-related metabolic outcomes. FKBP51 is highly expressed and regulated in the hypothalamus, the key brain region controlling metabolic regulation, but a functional characterization of hypothalamic FKBP51 and its impact on metabolic control is so far missing. Recently, FKBP51 was identified as a molecular hub, linking the stress response to homeostatic autophagy. Autophagy is a catabolic process for the degradation of misfolded or aggregated macromolecules and organelles in cells. Due to its upstream regulators like AMPK and mTOR, autophagy is tightly controlled by nutrients or starvation and has a large impact on metabolism. Glucocorticoid (GC) signalling has been reported to influence autophagic capacity and using the chaperone system, in accordance with FKBP51, can modulate homeostasis and metabolism. Based on recent evidence and our unpublished preliminary findings, we propose that hypothalamic FKBP51 may serve as a central regulator of stress-related metabolic phenotypes. We hypothesize that specific neuronal populations in hypothalamic nuclei such as the VMH and ARC will contribute in a distinct and differential way to the stress-related and FKBP51-mediated metabolic outcomes through induction of autophagy. Combining molecular, cellular, circuit and physiological approaches, the main objective of this proposal is to advance the knowledge on the role of FKBP51 in mediating the metabolic effects of stress exposures in hypothalamic nuclei, thereby unraveling the contribution of FKBP51 in the susceptibility or resilience to stress-related metabolic disorders.

• DFG Programme: Research Grants