Deletion of the glucocorticoid receptor chaperone FKBP51 prevents glucocorticoid-induced skin atrophy.

FKBP51 (FK506-binding protein 51) is a known co-chaperone and regulator of the glucocorticoid receptor (GR), which usually attenuates its activity. FKBP51 is one of the major GR target genes in skin, but its role in clinical effects of glucocorticoids is not known. Here, we used FKBP51 knockout (KO) mice to determine FKBP51's role in the major adverse effect of topical glucocorticoids, skin atrophy.

Marrow Fat-a New Target to Treat Bone Diseases?

Purpose Of Review: The goal of this review is to summarize recent findings on marrow adipose tissue (MAT) function and to discuss the possibility of targeting MAT for therapeutic purposes.

Recent Findings: MAT is characterized with high heterogeneity which may suggest both that marrow adipocytes originate from multiple different progenitors and/or their phenotype is determined by skeletal location and environmental cues. Close relationship to osteoblasts and heterogeneity suggests that MAT consists of cells representing spectrum of phenotypes ranging from lipid-filled adipocytes to pre-osteoblasts.

Reciprocal regulation of PPARγ and RUNX2 activities in marrow mesenchymal stem cells: Fine balance between p38 MAPK and Protein Phosphatase 5.

Purpose Of Review: Post-translational modifications (PTMs), specifically serine phosphorylation, are essential for determination and tuning up an activity of many proteins, including those that are involved in the control of gene transcription. Transcription factors PPARγ2 and RUNX2 are essential for mesenchymal stem cell (MSC) commitment to either adipocyte or osteoblast lineage. This review is summarizing current knowledge how serine phosphorylation PTMs regulate activities of both transcription factors and MSCs lineage commitment.

Marrow Adipose Tissue: Skeletal Location, Sexual Dimorphism, and Response to Sex Steroid Deficiency.

Marrow adipose tissue (MAT) is unique with respect to origin, metabolism, and function. MAT is characterized with high heterogeneity which correlates with skeletal location and bone metabolism. This fat depot is also highly sensitive to various hormonal, environmental, and pharmacologic cues to which it responds with changes in volume and/or metabolic phenotype.

Glucocorticoid Receptor β Induces Hepatic Steatosis by Augmenting Inflammation and Inhibition of the Peroxisome Proliferator-activated Receptor (PPAR) α.

Glucocorticoids (GCs) regulate energy supply in response to stress by increasing hepatic gluconeogenesis during fasting. Long-term GC treatment induces hepatic steatosis and weight gain. GC signaling is coordinated via the GC receptor (GR) GRα, as the GRβ isoform lacks a ligand-binding domain.

Protein Phosphatase PP5 Controls Bone Mass and the Negative Effects of Rosiglitazone on Bone through Reciprocal Regulation of PPARγ (Peroxisome Proliferator-activated Receptor γ) and RUNX2 (Runt-related Transcription Factor 2).

Peroxisome proliferator-activated receptor γ (PPARγ) and runt-related transcription factor 2 (RUNX2) are key regulators of mesenchymal stem cell (MSC) differentiation toward adipocytes and osteoblasts, respectively. Post-translational modifications of these factors determine their activities. Dephosphorylation of PPARγ at Ser-112 is required for its adipocytic activity, whereas phosphorylation of RUNX2 at serine 319 (Ser-319) promotes its osteoblastic activity.

FKBP51 Null Mice Are Resistant to Diet-Induced Obesity and the PPARγ Agonist Rosiglitazone.

FK506-binding protein-51 (FKBP51) is a molecular cochaperone recently shown to be a positive regulator of peroxisome proliferator-activated receptor (PPAR)γ, the master regulator of adipocyte differentiation and function. In cellular models of adipogenesis, loss of FKBP51 not only reduced PPARγ activity but also reduced lipid accumulation, suggesting that FKBP51 knock-out (KO) mice might have insufficient development of adipose tissue and lipid storage ability. This model was tested by examining wild-type (WT) and FKBP51-KO mice under regular and high-fat diet conditions.

PPARG Post-translational Modifications Regulate Bone Formation and Bone Resorption.

The peroxisome proliferator-activated receptor gamma (PPARγ) regulates osteoblast and osteoclast differentiation, and is the molecular target of thiazolidinediones (TZDs), insulin sensitizers that enhance glucose utilization and adipocyte differentiation. However, clinical use of TZDs has been limited by side effects including a higher risk of fractures and bone loss. Here we demonstrate that the same post-translational modifications at S112 and S273, which influence PPARγ pro-adipocytic and insulin sensitizing activities, also determine PPARγ osteoblastic (pS112) and osteoclastic (pS273) activities.

High bone mass in adult mice with diet-induced obesity results from a combination of initial increase in bone mass followed by attenuation in bone formation; implications for high bone mass and decreased bone quality in obesity.

Obesity is generally recognized as a condition which positively influences bone mass and bone mineral density (BMD). Positive effect of high body mass index (BMI) on bone has been recognized as a result of increased mechanical loading exerted on the skeleton. However, epidemiologic studies indicate that obesity is associated with increased incidence of fractures.

Analysis of FK506, timcodar (VX-853) and FKBP51 and FKBP52 chaperones in control of glucocorticoid receptor activity and phosphorylation.

The immunosuppressive ligand FK506 and the FK506-binding protein FKBP52 are stimulatory to glucocorticoid receptor (GR) activity. Here, we explore the underlying mechanism by comparing GR activity and phosphorylation status in response to FK506 and the novel nonimmunosuppressive ligand timcodar (VX-853) and in the presence and absence of FKBP52 and the closely related protein FKBP51. Using mouse embryonic fibroblast cells (MEFs) deficient knockout (KO) in FKBP51 or FKBP52, we show decreased GR activity at endogenous genes in 52KO cells, but increased activity in 51KO cells.

Bone and fat: a relationship of different shades.

Environmental and behavioral changes which occurred over the last century led simultaneously to a remarkable increase in human lifespan and to the development of health problems associated with functional impairment of organs either regulating or dependent on balanced energy metabolism. Diseases such as diabetes, obesity and osteoporosis are prevalent in our society and pose major challenges with respect to the overall health and economy. Therefore, better understanding of regulatory axes between bone and fat may provide the basis for development of strategies which will treat these diseases simultaneously and improve health and life quality of elderly.

FKBP51 reciprocally regulates GRα and PPARγ activation via the Akt-p38 pathway.

FK506-binding protein 51 (FKBP51) is a negative regulator of glucocorticoid receptor-α (GRα), although the mechanism is unknown. We show here that FKBP51 is also a chaperone to peroxisome proliferator-activated receptor-γ (PPARγ), which is essential for activity, and uncover the mechanism underlying this differential regulation. In COS-7 cells, FKBP51 overexpression reduced GRα activity at a glucocorticoid response element-luciferase reporter, while increasing PPARγ activity at a peroxisome proliferator response element reporter.

FKBP51 controls cellular adipogenesis through p38 kinase-mediated phosphorylation of GRα and PPARγ.

Glucocorticoid receptor-α (GRα) and peroxisome proliferator-activated receptor-γ (PPARγ) are critical regulators of adipogenic responses. We have shown that FK506-binding protein 51 (FKBP51) represses the Akt-p38 kinase pathway to reciprocally inhibit GRα but stimulate PPARγ by targeting serine 112 (PPARγ) and serines 220 and 234 (GRα). Here, this mechanism is shown to be essential for GRα and PPARγ control of cellular adipogenesis.

Glucocorticoid receptor β stimulates Akt1 growth pathway by attenuation of PTEN.

Glucocorticoids (GCs) are known inhibitors of proliferation and are commonly prescribed to cancer patients to inhibit tumor growth and induce apoptosis via the glucocorticoid receptor (GR). Because of alternative splicing, the GR exists as two isoforms, GRα and GRβ. The growth inhibitory actions of GCs are mediated via GRα, a hormone-induced transcription factor.

Partial agonist, telmisartan, maintains PPARγ serine 112 phosphorylation, and does not affect osteoblast differentiation and bone mass.

Peroxisome proliferator activated receptor gamma (PPARγ) controls both glucose metabolism and an allocation of marrow mesenchymal stem cells (MSCs) toward osteoblast and adipocyte lineages. Its activity is determined by interaction with a ligand which directs posttranscriptional modifications of PPARγ protein including dephosphorylation of Ser112 and Ser273, which results in acquiring of pro-adipocytic and insulin-sensitizing activities, respectively. PPARγ full agonist TZD rosiglitazone (ROSI) decreases phosphorylation of both Ser112 and Ser273 and its prolonged use causes bone loss in part due to diversion of MSCs differentiation from osteoblastic toward adipocytic lineage.

PPARδ binding to heme oxygenase 1 promoter prevents angiotensin II-induced adipocyte dysfunction in Goldblatt hypertensive rats.

Objective: Renin-angiotensin system (RAS) regulates adipogenic response with adipocyte hypertrophy by increasing oxidative stress. Recent studies have shown the role of peroxisome proliferator-activated receptor-δ (PPARδ) agonist in attenuation of angiotensin II-induced oxidative stress. The aim of this study was to explore a potential mechanistic link between PPARδ and the cytoprotective enzyme heme oxygenase-1 (HO-1) and to elucidate the contribution of HO-1 to the adipocyte regulatory effects of PPARδ agonism in an animal model of enhanced RAS, the Goldblatt 2 kidney 1 clip (2K1C) model.

Protein phosphatase 5 mediates lipid metabolism through reciprocal control of glucocorticoid receptor and peroxisome proliferator-activated receptor-γ (PPARγ).

Glucocorticoid receptor-α (GRα) and peroxisome proliferator-activated receptor-γ (PPARγ) regulate adipogenesis by controlling the balance between lipolysis and lipogenesis. Here, we show that protein phosphatase 5 (PP5), a nuclear receptor co-chaperone, reciprocally modulates the lipometabolic activities of GRα and PPARγ. Wild-type and PP5-deficient (KO) mouse embryonic fibroblast cells were used to show binding of PP5 to both GRα and PPARγ.

FKBP51-a selective modulator of glucocorticoid and androgen sensitivity.

FK506-binding protein 51 (FKBP51) is gaining increased recognition for its essential roles in cell biology. Originally discovered as a component of steroid receptor complexes, it is now known to regulate a diverse set of transcription factors, enzymes and structural proteins. Its cellular properties suggest numerous possible functions for FKBP51 in physiology, and the best clue to its potential importance may be the following: FKBP51 is a glucocorticoid-induced negative regulator of the glucocorticoid receptor.

Discovery of glucocorticoid receptor-beta in mice with a role in metabolism.

Glucocorticoid hormones control diverse physiological processes, including metabolism and immunity, by activating the major glucocorticoid receptor (GR) isoform, GRalpha. However, humans express an alternative isoform, human (h)GRbeta, that acts as an inhibitor of hGRalpha to produce a state of glucocorticoid resistance. Indeed, evidence exists that hGRbeta contributes to many diseases and resistance to glucocorticoid hormone therapy.

Susceptibility to diet-induced hepatic steatosis and glucocorticoid resistance in FK506-binding protein 52-deficient mice.

Although FK506-binding protein 52 (FKBP52) is an established positive regulator of glucocorticoid receptor (GR) activity, an in vivo role for FKBP52 in glucocorticoid control of metabolism has not been reported. To address this question, FKBP52(+/-) mice were placed on a high-fat (HF) diet known to induce obesity, hepatic steatosis, and insulin resistance. Tissue profiling of wild-type mice showed high levels of FKBP52 in the liver but little to no expression in muscle or adipose tissue, predicting a restricted pattern of FKBP52 effects on metabolism.