Tissue-specific deletion of FKBP51 reveals distinct roles in stress responsivity and metabolic regulation
5 affiliations
- 1Research Group Neurobiology of Stress Resilience, Max Planck Institute of Psychiatry, 80807 Munich, Germany
- 2International Max Planck Research School for Translational Psychiatry (IMPRS-TP), Munich, Germany
- 3Graduate School of Systemic Neurosciences, Ludwig Maximilians University (GSN-LMU), Munich, Germany
- 4Neurohomeostasis Research Group, Department of Psychiatry and Psychotherapy, University Hospital Bonn, Bonn, Germany
- 5Amsterdam Institute for Life and Environment, Environmental Health and Toxicology, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
Abstract
The co-chaperone FKBP51 serves as a critical molecular intersection between environmental stress and metabolic health, yet the specific tissue-level mechanisms driving its systemic effects remain poorly understood. While global FKBP51 deficiency provides robust protection against diet-induced obesity and insulin resistance, this study aimed to isolate the contributions of the brain, skeletal muscle, and adipose tissue using targeted knockout mouse models, cellular assays, and Caenorhabditis elegans. In cellular models, both pharmacological antagonism and genetic deletion of FKBP51 enhanced glucose uptake, and silencing its ortholog in C. elegans led to increased lipid accumulation, supporting a conserved role in energy metabolism. Neural-specific FKBP51 deletion in mice successfully blunted corticosterone secretion during acute stress, confirming its role in HPA axis regulation, but it did not alter body weight or glucose metabolism under either standard or high-fat diets. Similarly, the deletion of FKBP51 exclusively in adipocytes or muscle failed to impact weight regulation, body composition, or systemic insulin sensitivity. Even the simultaneous deletion of FKBP51 in both adipose and muscle tissues resulted in only minor, sex-specific metabolic shifts, failing to recapitulate the strong phenotype of full-body knockouts. These results indicate that the metabolic protection associated with FKBP51 loss is likely an emergent property of synchronized multi-organ signaling rather than the action of a single dominant tissue. Consequently, effective therapeutic targeting of the FKBP51-stress-metabolism axis may require the concurrent modulation of both central neuroendocrine pathways and peripheral metabolic systems.
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BibTeX
@article{springer2026tissuespecific,
title = {{Tissue-specific deletion of FKBP51 reveals distinct roles in stress responsivity and metabolic regulation}},
author = {Margherita Springer and Lea M. Brix and Veronika Kovarova and Sowmya Narayan and Daniela Harbich and Benjamin Haworth and Fatima Feyzanur Mete and Daniel Suñer-Rubio and Sara Stanciu and London Aman and Minnah Irfan and Benjamin Jurek and Shiladitya Mitra and Lotte van Doeselaar and Huanqing Yang and Alessandra Bianco and Maria Clara Sokn and Nils C. Gassen and Samantha Hughes and Mathias V. Schmidt},
journal = {Molecular Metabolism},
year = {2026},
month = oct,
doi = {10.1016/j.molmet.2026.102455},
url = {https://doi.org/10.1016/j.molmet.2026.102455},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Tissue-specific deletion of FKBP51 reveals distinct roles in stress responsivity and metabolic regulation
AU - Margherita Springer
AU - Lea M. Brix
AU - Veronika Kovarova
AU - Sowmya Narayan
AU - Daniela Harbich
AU - Benjamin Haworth
AU - Fatima Feyzanur Mete
AU - Daniel Suñer-Rubio
AU - Sara Stanciu
AU - London Aman
AU - Minnah Irfan
AU - Benjamin Jurek
AU - Shiladitya Mitra
AU - Lotte van Doeselaar
AU - Huanqing Yang
AU - Alessandra Bianco
AU - Maria Clara Sokn
AU - Nils C. Gassen
AU - Samantha Hughes
AU - Mathias V. Schmidt
PY - 2026
DA - 2026/10/08
JO - Molecular Metabolism
DO - 10.1016/j.molmet.2026.102455
UR - https://doi.org/10.1016/j.molmet.2026.102455
AB - The co-chaperone FKBP51 serves as a critical molecular intersection between environmental stress and metabolic health, yet the specific tissue-level mechanisms driving its systemic effects remain poorly understood. While global FKBP51 deficiency provides robust protection against diet-induced obesity and insulin resistance, this study aimed to isolate the contributions of the brain, skeletal muscle, and adipose tissue using targeted knockout mouse models, cellular assays, and Caenorhabditis elegans. In cellular models, both pharmacological antagonism and genetic deletion of FKBP51 enhanced glucose uptake, and silencing its ortholog in C. elegans led to increased lipid accumulation, supporting a conserved role in energy metabolism. Neural-specific FKBP51 deletion in mice successfully blunted corticosterone secretion during acute stress, confirming its role in HPA axis regulation, but it did not alter body weight or glucose metabolism under either standard or high-fat diets. Similarly, the deletion of FKBP51 exclusively in adipocytes or muscle failed to impact weight regulation, body composition, or systemic insulin sensitivity. Even the simultaneous deletion of FKBP51 in both adipose and muscle tissues resulted in only minor, sex-specific metabolic shifts, failing to recapitulate the strong phenotype of full-body knockouts. These results indicate that the metabolic protection associated with FKBP51 loss is likely an emergent property of synchronized multi-organ signaling rather than the action of a single dominant tissue. Consequently, effective therapeutic targeting of the FKBP51-stress-metabolism axis may require the concurrent modulation of both central neuroendocrine pathways and peripheral metabolic systems.
SN - 2212-8778
ER -