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. We propose a term of adiposteoblast for describing phenotypic spectrum of MAT. Manipulating with MAT activity in diseases where impairment in energy metabolism correlates with bone functional deficit, such as aging and diabetes, may be beneficial for both. Paracrine activities of MAT might be considered for treatment of bone diseases. MAT has unrecognized potential, either beneficial or detrimental, to regulate bone homeostasis in physiological and pathological conditions. More research is required to harness this potential for therapeutic purposes.

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. Here we show that protein phosphatase 5 (PP5) reciprocally regulates each receptor by targeting each serine. Mice deficient in PP5 phosphatase have increased osteoblast numbers and high bone formation, which results in high bone mass in the appendicular and axial skeleton. This is associated with a substantial decrease in lipid-containing marrow adipocytes. Indeed, in the absence of PP5 the MSC lineage allocation is skewed toward osteoblasts and away from lipid accumulating adipocytes, although an increase in beige adipocyte gene expression is observed. In the presence of rosiglitazone, PP5 translocates to the nucleus, binds to PPARγ and RUNX2, and dephosphorylates both factors, resulting in activation of PPARγ adipocytic and suppression of RUNX2 osteoblastic activities. Moreover, shRNA knockdown of PP5 results in cells refractory to rosiglitazone treatment. Lastly, mice deficient in PP5 are resistant to the negative effects of rosiglitazone on bone, which in wild type animals causes a 50% decrease in trabecular bone mass. In conclusion, PP5 is a unique phosphatase reciprocally regulating PPARγ and RUNX2 activities in marrow MSC.

Glucocorticoid Receptor ß 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 GRß isoform lacks a ligand-binding domain. The roles of the GR isoforms in the regulation of lipid accumulation is unknown. The purpose of this study was to determine whether GRß inhibits the actions of GCs in the liver, or enhances hepatic lipid accumulation. We show that GRß expression is increased in adipose and liver tissues in obese high-fat fed mice. Adenovirus-mediated delivery of hepatic GRß overexpression (GRß-Ad) resulted in suppression of gluconeogenic genes and hyperglycemia in mice on a regular diet. Furthermore, GRß-Ad mice had increased hepatic lipid accumulation and serum triglyceride levels possibly due to the activation of NF-κB signaling and increased tumor necrosis factor α (TNFα) and inducible nitric-oxide synthase expression, indicative of enhanced M1 macrophages and the development of steatosis. Consequently, GRß-Ad mice had increased glycogen synthase kinase 3ß (GSK3ß) activity and reduced hepatic PPARα and fibroblast growth factor 21 (FGF21) expression and lower serum FGF21 levels, which are two proteins known to increase during fasting to enhance the burning of fat by activating the ß-oxidation pathway. In conclusion, GRß antagonizes the GC-induced signaling during fasting via GRα and the PPARα-FGF21 axis that reduces fat burning. Furthermore, hepatic GRß increases inflammation, which leads to hepatic lipid accumulation.

Glucocorticoid receptor ß 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 GRß. The growth inhibitory actions of GCs are mediated via GRα, a hormone-induced transcription factor. The GRß isoform, however, lacks helix 12 of the ligand-binding domain and cannot bind GCs. While we have previously shown that GRß mRNA is responsive to insulin, the role of GRß in insulin signaling and growth pathways is unknown. In the present study, we show that GRß suppresses PTEN expression, leading to enhanced insulin-stimulated growth. These characteristics were independent of the inhibitory qualities that have been reported for GRß on GRα. Additionally, we found that GRß increased phosphorylation of Akt basally, which was further amplified following insulin treatment. In particular, GRß specifically targets Akt1 in growth pathways. Our results demonstrate that the GRß/Akt1 axis is a major player in insulin-stimulated growth.

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.

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. In response to adipogenic stimuli, PP5-KO mouse embryonic fibroblast cells showed almost no lipid accumulation with reduced expression of adipogenic markers (aP2, CD36, and perilipin) and low fatty-acid synthase enzymatic activity. This was completely reversed following reintroduction of PP5. Loss of PP5 increased phosphorylation of GRα at serines 212 and 234 and elevated dexamethasone-induced activity at prolipolytic genes. In contrast, PPARγ in PP5-KO cells was hyperphosphorylated at serine 112 but had reduced rosiglitazone-induced activity at lipogenic genes. Expression of the S112A mutant rescued PPARγ transcriptional activity and lipid accumulation in PP5-KO cells pointing to Ser-112 as an important residue of PP5 action. This work identifies PP5 as a fulcrum point in nuclear receptor control of the lipolysis/lipogenesis equilibrium and as a potential target in the treatment of obesity.

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. Unexpectedly, we found that all skin compartments (epidermis, dermis, dermal adipose and CD34+ stem cells) in FKBP51 KO animals were much more resistant to glucocorticoid-induced hypoplasia. Furthermore, despite the absence of inhibitory FKBP51, the basal level of expression and glucocorticoid activation of GR target genes were not increased in FKBP51 KO skin or CRISPR/Cas9-edited FKBP51 KO HaCaT human keratinocytes. FKBP51 is known to negatively regulate Akt and mTOR. We found a significant increase in AktSer473 and mTORSer2448 phosphorylation and downstream pro-growth signaling in FKBP51-deficient keratinocytes in vivo and in vitro. As Akt/mTOR-GR crosstalk is usually negative in skin, our results suggest that Akt/mTOR activation could be responsible for the lack of increased GR function and resistance of FKBP51 KO mice to the steroid-induced skin atrophy.

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. RECENT FINDING: Both PPARγ2 and RUNX2 transcriptional activities are regulated by similar PTMs, however with an opposite outcome. The same p38 MAPK mediates serine phosphorylation that leads to activation of RUNX2 and inactivation of PPARγ2. The process of protein phosphorylation is balanced with a process of protein dephosphorylation. Protein phosphatase 5 simultaneously dephosphorylates both proteins, which results in activation of PPARγ2 and inactivation of RUNX2. SUMMARY: This review provides a summary of the "yinyang" fine-tuned mechanism by which p38 MAPK and PP5 regulate 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. We have demonstrated previously that MAT has characteristics of both white (WAT) and brown (BAT)-like or beige adipose tissue, and that beige phenotype is attenuated with aging and in diabetes. Here, we extended our analysis by comparing MAT phenotype in different locations within a tibia bone of mature C57BL/6 mice and with respect to the presence of sex steroids in males and females. We report that MAT juxtaposed to trabecular bone of proximal tibia (pMAT) is characterized by elevated expression of beige fat markers including Ucp1, HoxC9, Prdm16, Tbx1, and Dio2, when compared with MAT located in distal tibia (dMAT). There is also a difference in tissue organization with adipocytes in proximal tibia being dispersed between trabeculae, while adipocytes in distal tibia being densely packed. Higher trabecular bone mass (BV/TV) in males correlates with lower pMAT volume and higher expression of beige markers in the same location, when compared with females. However, there is no sexual divergence in the volume and transcriptional profile of dMAT. A removal of ovaries in females resulted in decreased cortical bone mass and increased volume of both pMAT and dMAT, as well as volume of gonadal WAT (gWAT). Increase in pMAT volume was associated with marked increase in Fabp4 and Adiponectin expression and relative decrease in beige fat gene markers. A removal of testes in males resulted in cortical and trabecular bone loss and the tendency to increased volume of both pMAT and dMAT, despite a loss of gWAT. Orchiectomy did not affect the expression of white and beige adipocyte gene markers. In conclusion, expression profile of beige adipocyte gene markers correlates with skeletal location of active bone remodeling and higher BV/TV, however bone loss resulted from sex steroid deficiency is not proportional to MAT expansion at the same skeletal location.

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. Under both diets, FKBP51-KO mice were resistant to weight gain, hepatic steatosis, and had greatly reduced white adipose tissue (WAT) but higher amounts of brown adipose tissue. Under high-fat diet, KO mice were highly resistant to adiposity and exhibited reduced plasma lipids and elevated glucose and insulin tolerance. Profiling of perigonadal and sc WAT revealed elevated expression of brown adipose tissue lineage genes in KO mice that correlated increased energy expenditure and a shift of substrate oxidation to carbohydrates, as measured by indirect calorimetry. To directly test PPARγ involvement, WT and KO mice were fed rosiglitazone agonist. In WT mice, rosiglitazone induced whole-body weight gain, increased WAT mass, a shift of substrate oxidation to lipids, and elevated expression of PPARγ-regulated lipogenic genes in WAT. In contrast, KO mice had reduced rosiglitazone responses for these parameters. Our results identify FKBP51 as an important regulator of PPARγ in WAT and as a potential new target in the treatment of obesity and diabetes.

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. In 52KO cells, elevated phosphorylation occurred at inhibitory serine 212 and decreased phosphorylation at the stimulatory S220 residue. In contrast, 51KO cells showed increased GR phosphorylation at the stimulatory residues S220 and S234. In wild-type (WT) MEF cells, timcodar, like FK506, potentiated dexamethasone-induced GR transcriptional activity at two endogenous genes. Using 52KO and 51KO MEF cells, FK506 potentiated GR activity in 51KO cells but could not do so in 52KO cells, suggesting FKBP52 as the major target of FK506 action. Like FK506, timcodar potentiated GR in 51KO cells, but it also increased GR activity in 52KO cells. Knock-down of FKBP51 in the 52KO cells showed that the latter effect of timcodar required FKBP51. Thus, timcodar appears to have a dual specificity for FKBP51 and FKBP52. This work demonstrates phosphorylation as an important mechanism in FKBP control of GR and identifies the first nonimmunosuppressive macrolide capable of targeting GR action.

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. Telmisartan (TEL), an anti-hypertensive drug from the class of angiotensin receptor blockers, also acts as a partial PPARγ agonist with insulin-sensitizing and a weak pro-adipocytic activity. TEL decreased S273pPPARγ and did not affect S112pPPARγ levels in a model of marrow MSC differentiation, U-33/γ2 cells. In contrast to ROSI, TEL did not affect osteoblast phenotype and actively blocked ROSI-induced anti-osteoblastic activity and dephosphorylation of S112pPPARγ. The effect of TEL on bone was tested side-by-side with ROSI. In contrast to ROSI, TEL administration did not affect bone mass and bone biomechanical properties measured by micro-indentation method and did not induce fat accumulation in bone, and it partially protected from ROSI-induced bone loss. In addition, TEL induced "browning" of epididymal white adipose tissue marked by increased expression of UCP1, FoxC2, Wnt10b and IGFBP2 and increased overall energy expenditure. These studies point to the complexity of mechanisms by which PPARγ acquires anti-osteoblastic and pro-adipocytic activities and suggest an importance of Ser112 phosphorylation status as being a part of the mechanism regulating this process. These studies showed that TEL acts as a full PPARγ agonist for insulin-sensitizing activity and as a partial agonist/partial antagonist for pro-adipocytic and anti-osteoblastic activities. They also suggest a relationship between PPARγ fat "browning" activity and a lack of anti-osteoblastic activity.

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. In 3T3-L1 cells, FKBP51 was a prominent marker of the differentiated state and knockdown of FKBP51 showed reduced lipid accumulation and expression of adipogenic genes. Compared with wild-type (WT), FKBP51 knockout (51KO) mouse embryonic fibroblasts (MEFs) showed dramatic resistance to differentiation, with almost no lipid accumulation and greatly reduced adipogenic gene expression. These features were rescued by reexpression of FKBP51 in 51KO cells. 51KO MEFs exhibited reduced fatty acid synthase activity, increased sensitivity to GRα-induced lipolysis, and reduced PPARγ activity at adipogenic genes (adiponectin, CD36, and perilipin) but elevated GRα transrepression at these same genes. A p38 kinase inhibitor increased lipid content in WT cells and also restored lipid levels in 51KO cells, showing that elevated p38 kinase activity is a major contributor to adipogenic resistance in the 51KO cells. In 51KO cells, the S112A mutant of PPARγ and the triple S212A/S220A/S234A mutant of GRα both increased lipid accumulation, identifying these residues as targets of the FKBP51/p38 axis. Our combined investigations have uncovered FKBP51 as a key regulator of adipogenesis via the Akt-p38 pathway and as a potential target in the treatment of obesity and related disorders.

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. Conversely, FKBP51-deficient (knockout) (51KO) mouse embryonic fibroblasts (MEFs) showed elevated GRα but reduced PPARγ activities compared with those in wild-type MEFs. Phosphorylation is known to exert a similar pattern of reciprocal modulation of GRα and PPARγ. Knockdown of FKBP51 in 3T3-L1 preadipocytes increased phosphorylation of PPARγ at serine 112, a phospho-residue that inhibits activity. In 51KO cells, elevated phosphorylation of GRα at serines 220 and 234, phospho-residues that promote activity, was observed. Because FKBP51 is an essential chaperone to the Akt-specific phosphatase PH domain leucine-rich repeat protein phosphatase, Akt signaling was investigated. Elevated Akt activation and increased activation of p38 kinase, a downstream target of Akt that phosphorylates GRα and PPARγ, were seen in 51KO MEFs, causing activation and inhibition, respectively. Inactivation of p38 with PD169316 reversed the effects of FKBP51 deficiency on GRα and PPARγ activities and reduced PPARγ phosphorylation. Last, loss of FKBP51 caused a shift of PPARγ from cytoplasm to nucleus, as previously shown for GRα. A model is proposed in which FKBP51 loss reciprocally regulates GRα and PPARγ via 2 complementary mechanisms: activation of Akt-p38-mediated phosphorylation and redistribution of the receptors to the nucleus for direct targeting by p38.

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. Thus, FKBP51 is intricately involved in regulation of the most pleiotropic hormone known to biology. In contrast to glucocorticoid receptor, FKBP51 is a positive regulator of the androgen receptor, suggesting that it functions as a reciprocal modulator of glucocorticoid-mediated and androgen-mediated physiology. In this work, we evaluate this hypothesis by examining recent cellular and physiological evidence.

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. However, rigorous testing of the GRbeta contribution has not been possible, because rodents, especially mice, are not thought to express the beta-isoform. Here, we report expression of GRbeta mRNA and protein in the mouse. The mGRbeta isoform arises from a distinct alternative splicing mechanism utilizing intron 8, rather than exon 9 as in humans. The splicing event produces a form of beta that is similar in structure and functionality to hGRbeta. Mouse (m)GRbeta has a degenerate C-terminal region that is the same size as hGRbeta. Using a variety of newly developed tools, such as a mGRbeta-specific antibody and constructs for overexpression and short hairpin RNA knockdown, we demonstrate that mGRbeta cannot bind dexamethasone agonist, is inhibitory of mGRalpha, and is up-regulated by inflammatory signals. These properties are the same as reported for hGRbeta. Additionally, novel data is presented that mGRbeta is involved in metabolism. When murine tissue culture cells are treated with insulin, no effect on mGRalpha expression was observed, but GRbeta was elevated. In mice subjected to fasting-refeeding, a large increase of GRbeta was seen in the liver, whereas mGRalpha was unchanged. This work uncovers the much-needed rodent model of GRbeta for investigations of physiology and disease.

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. In response to HF, FKBP52(+/-) mice demonstrated a susceptibility to hyperglycemia and hyperinsulinemia that correlated with reduced insulin clearance and reduced expression of hepatic CEACAM1 (carcinoembryonic antigen-related cell adhesion molecule 1), a mediator of clearance. Livers of HF-fed mutant mice had high lipid content and elevated expression of lipogenic genes (peroxisome proliferator-activated receptor gamma, fatty acid synthase, and sterol regulatory element-binding protein 1c) and inflammatory markers (TNFalpha). Interestingly, mutant mice under HF showed elevated serum corticosterone, but their steatotic livers had reduced expression of gluconeogenic genes (phosphoenolpyruvate carboxy kinase, glucose 6 phosphatase, and pyruvate dehydrogenase kinase 4), whereas muscle and adipose expressed normal to elevated levels of glucocorticoid markers. These data suggest a state of glucocorticoid resistance arising from liver-specific loss of GR activity. Consistent with this hypothesis, reduced expression of gluconeogenic genes and CEACAM1 was observed in dexamethasone-treated FKBP52-deficient mouse embryonic fibroblast cells. We propose a model in which FKBP52 loss reduces GR control of gluconeogenesis, predisposing the liver to steatosis under HF-diet conditions attributable to a shunting of metabolism from glucose production to lipogenesis.