TY - JOUR
T1 - The co-chaperone FKBP51 modulates HPA axis activity and age-related maladaptation of the stress system in pituitary proopiomelanocortin cells
AU - Brix, Lea M.
AU - Häusl, Alexander S.
AU - Toksöz, Irmak
AU - Bordes, Joeri
AU - van Doeselaar, Lotte
AU - Engelhardt, Clara
AU - Narayan, Sowmya
AU - Springer, Margherita
AU - Sterlemann, Vera
AU - Deussing, Jan M.
AU - Chen, Alon
AU - Schmidt, Mathias V.
PY - 2022/4
Y1 - 2022/4
N2 - Glucocorticoid (GC)-mediated negative feedback of the hypothalamic-pituitary-adrenal (HPA) axis, the body’s physiological stress response system, is tightly regulated and essential for appropriate termination of this hormonal cascade. Disturbed regulation and maladaptive response of this axis are fundamental components of multiple stress-induced psychiatric and metabolic diseases and aging. The co-chaperone FK506 binding protein 51 (FKBP51) is a negative regulator of the GC receptor (GR), is highly stress responsive, and its polymorphisms have been repeatedly associated with stress-related disorders and dysfunctions in humans and rodents. Proopiomelanocortin (Pomc)-expressing corticotropes in the anterior pituitary gland are one of the key cell populations of this closed-loop GC-dependent negative feedback regulation of the HPA axis in the periphery. However, the cell type-specific role of FKBP51 in anterior pituitary corticotrope POMC cells and its impact on age-related HPA axis disturbances are yet to be elucidated. Here, using a combination of endogenous knockout and viral rescue, we show that male mice lacking FKBP51 in Pomc-expressing cells exhibit enhanced GR-mediated negative feedback and are protected from age-related disruption of their diurnal corticosterone (CORT) rhythm. Our study highlights the complexity of tissue- and cell type-specific, but also cross-tissue effects of FKBP51 in the rodent stress response at different ages and extends our understanding of potential targets for pharmacological intervention in stress- and age-related disorders.
AB - Glucocorticoid (GC)-mediated negative feedback of the hypothalamic-pituitary-adrenal (HPA) axis, the body’s physiological stress response system, is tightly regulated and essential for appropriate termination of this hormonal cascade. Disturbed regulation and maladaptive response of this axis are fundamental components of multiple stress-induced psychiatric and metabolic diseases and aging. The co-chaperone FK506 binding protein 51 (FKBP51) is a negative regulator of the GC receptor (GR), is highly stress responsive, and its polymorphisms have been repeatedly associated with stress-related disorders and dysfunctions in humans and rodents. Proopiomelanocortin (Pomc)-expressing corticotropes in the anterior pituitary gland are one of the key cell populations of this closed-loop GC-dependent negative feedback regulation of the HPA axis in the periphery. However, the cell type-specific role of FKBP51 in anterior pituitary corticotrope POMC cells and its impact on age-related HPA axis disturbances are yet to be elucidated. Here, using a combination of endogenous knockout and viral rescue, we show that male mice lacking FKBP51 in Pomc-expressing cells exhibit enhanced GR-mediated negative feedback and are protected from age-related disruption of their diurnal corticosterone (CORT) rhythm. Our study highlights the complexity of tissue- and cell type-specific, but also cross-tissue effects of FKBP51 in the rodent stress response at different ages and extends our understanding of potential targets for pharmacological intervention in stress- and age-related disorders.
UR - http://www.scopus.com/inward/record.url?scp=85123361441&partnerID=8YFLogxK
U2 - 10.1016/j.psyneuen.2022.105670
DO - 10.1016/j.psyneuen.2022.105670
M3 - مقالة
C2 - 35091292
SN - 0306-4530
VL - 138
JO - Psychoneuroendocrinology
JF - Psychoneuroendocrinology
M1 - 105670
ER -