Tissue-Specific Deletion of FKBP51 Reveals Distinct Roles in Stress Responsivity and Metabolic Regulation.

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.