Sex-specific and opposed effects of FKBP51 in glutamatergic and GABAergic neurons: Implications for stress susceptibility and resilience.

Mental health disorders often arise as a combination of environmental and genetic factors. The FKBP5 gene, encoding the GR co-chaperone FKBP51, has been uncovered as a key genetic risk factor for stress-related illness. However, the exact cell type and region-specific mechanisms by which FKBP51 contributes to stress resilience or susceptibility processes remain to be unravelled. FKBP51 functionality is known to interact with the environmental risk factors age and sex, but so far data on behavioral, structural, and molecular consequences of these interactions are still largely unknown. Here we report the cell type- and sex-specific contribution of FKBP51 to stress susceptibility and resilience mechanisms under the high-risk environmental conditions of an older age, by using two conditional knockout models within glutamatergic (Fkbp5Nex) and GABAergic (Fkbp5Dlx) neurons of the forebrain. Specific manipulation of Fkbp51 in these two cell types led to opposing effects on behavior, brain structure and gene expression profiles in a highly sex-dependent fashion. The results emphasize the role of FKBP51 as a key player in stress-related illness and the need for more targeted and sex-specific treatment strategies.

Structure-Based Discovery of a New Selectivity-Enabling Motif for the FK506-Binding Protein 51.

In recent years, the selective inhibition of FKBP51 has emerged as a possible treatment for chronic pain, obesity-induced diabetes, or depression. All currently known advanced FKBP51-selective inhibitors, including the widely used SAFit2, contain a cyclohexyl residue as a key motif for enabling selectivity over the closest homologue and anti-target FKBP52. During a structure-based SAR exploration, we surprisingly discovered thiophenes as highly efficient cyclohexyl replacement moieties that retain the strong selectivity of SAFit-type inhibitors for FKBP51 over FKBP52. Cocrystal structures revealed that the thiophene-containing moieties enable selectivity by stabilizing a flipped-out conformation of Phe67 of FKBP51. Our best compound, 19b, potently binds to FKBP51 biochemically as well as in mammalian cells, desensitize TRPV1 in primary sensory neurons, and has an acceptable PK profile in mice, suggesting its use as a novel tool compound for studying FKBP51 in animal models of neuropathic pain.

Analysis of the Selective Antagonist SAFit2 as a Chemical Probe for the FK506-Binding Protein 51.

The FK506-binding protein 51 (FKBP51) has emerged as an important regulator of the mammalian stress response and is involved in persistent pain states and metabolic pathways. The FK506 analog SAFit2 (short for selective antagonist of FKBP51 by induced fit) was the first potent and selective FKBP51 ligand with an acceptable pharmacokinetic profile. At present, SAFit2 represents the gold standard for FKBP51 pharmacology and has been extensively used in numerous biological studies. Here we review the current knowledge on SAFit2 as well as guidelines for its use.

Contribution of the co-chaperone FKBP51 in the ventromedial hypothalamus to metabolic homeostasis in male and female mice.

OBJECTIVE: Steroidogenic factor 1 (SF1) expressing neurons in the ventromedial hypothalamus (VMH) have been directly implicated in whole-body metabolism and in the onset of obesity. The co-chaperone FKBP51 is abundantly expressed in the VMH and was recently linked to type 2 diabetes, insulin resistance, adipogenesis, browning of white adipose tissue (WAT) and bodyweight regulation. METHODS: We investigated the role of FKBP51 in the VMH by conditional deletion and virus-mediated overexpression of FKBP51 in SF1-positive neurons. Baseline and high fat diet (HFD)-induced metabolic- and stress-related phenotypes in male and female mice were obtained. RESULTS: In contrast to previously reported robust phenotypes of FKBP51 manipulation in the entire mediobasal hypothalamus (MBH), selective deletion or overexpression of FKBP51 in the VMH resulted in only a moderate alteration of HFD-induced bodyweight gain and body composition, independent of sex. CONCLUSIONS: Overall, this study shows that animals lacking and overexpressing Fkbp5 in Sf1-expressing cells within the VMH display only a mild metabolic phenotype compared to an MBH-wide manipulation of this gene, suggesting that FKBP51 in SF1 neurons within this hypothalamic nucleus plays a subsidiary role in controlling whole-body metabolism.

The co-chaperone FKBP51 modulates HPA axis activity and age-related maladaptation of the stress system in pituitary proopiomelanocortin cells.

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.

Resveratrol and Its Human Metabolites-Effects on Metabolic Health and Obesity.

Resveratrol is one of the most widely studied polyphenols and it has been assigned a plethora of metabolic effects with potential health benefits. Given its low bioavailability and extensive metabolism, clinical studies using resveratrol have not always replicated in vitro observations. In this review, we discuss human metabolism and biotransformation of resveratrol, and reported molecular mechanisms of action, within the context of metabolic health and obesity. Resveratrol has been described as mimicking caloric restriction, leading to improved exercise performance and insulin sensitivity (increasing energy expenditure), as well as having a body fat-lowering effect by inhibiting adipogenesis, and increasing lipid mobilization in adipose tissue. These multi-organ effects place resveratrol as an anti-obesity bioactive of potential therapeutic use.

A robust neuromuscular system protects rat and human skeletal muscle from sarcopenia.

Declining muscle mass and function is one of the main drivers of loss of independence in the elderly. Sarcopenia is associated with numerous cellular and endocrine perturbations, and it remains challenging to identify those changes that play a causal role and could serve as targets for therapeutic intervention. In this study, we uncovered a remarkable differential susceptibility of certain muscles to age-related decline. Aging rats specifically lose muscle mass and function in the hindlimbs, but not in the forelimbs. By performing a comprehensive comparative analysis of these muscles, we demonstrate that regional susceptibility to sarcopenia is dependent on neuromuscular junction fragmentation, loss of motoneuron innervation, and reduced excitability. Remarkably, muscle loss in elderly humans also differs in vastus lateralis and tibialis anterior muscles in direct relation to neuromuscular dysfunction. By comparing gene expression in susceptible and non-susceptible muscles, we identified a specific transcriptomic signature of neuromuscular impairment. Importantly, differential molecular profiling of the associated peripheral nerves revealed fundamental changes in cholesterol biosynthetic pathways. Altogether our results provide compelling evidence that susceptibility to sarcopenia is tightly linked to neuromuscular decline in rats and humans, and identify dysregulation of sterol metabolism in the peripheral nervous system as an early event in this process.