Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of chronic liver-related morbidity and mortality. Though high fructose intake is acknowledged as a metabolic hazard, its role in the etiology of MASLD requires further clarification. Here, we demonstrated that high dietary fructose drives MASLD development and promotes MASLD progression in mice, and identified Usp2 as a fructose-responsive gene in the liver. Elevated USP2 levels were detected in the hepatocytes of MASLD mice; a similar increase was observed following fructose exposure in primary hepatocytes and mouse AML12 cells. Notably, hepatocytes overexpressing USP2 presented with exaggerated lipid accumulation and metabolic inflammation when exposed to fructose. Conversely, USP2 knockdown mitigated these fructose-induced changes. Furthermore, USP2 was found to activate the C/EBPα/11β-HSD1 signaling, which further impacted the equilibrium of cortisol and cortisone in the circulation of mice. Collectively, our findings revealed the role of dietary fructose in MASLD pathogenesis and identified the USP2-mediated C/EBPα/ 11β-HSD1 signaling as a potential target for the management of MASLD.

UNASSIGNED: Blood biomarkers are proposed as a diagnostic alternative to amyloid PET or cerebrospinal fluid (CSF) analyses for the diagnosis of Alzheimer\'s disease (AD). Relatively little is known of the natural history of patients identified by different blood biomarkers.
UNASSIGNED: To identify patients with elevated plasma phosphorylated tau (pTau)181 from a prior Phase 2a trial, and explore the natural histories of their clinical progression, and potential efficacy of Xanamem, a selective inhibitor of 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in these patients.
UNASSIGNED: A prespecified, double-blind analysis was conducted in 72 participants with clinically diagnosed AD and available plasma samples from baseline and Week 12 of the \"XanADu\" Phase 2a trial of Xanamem versus placebo. The analysis prespecified plasma pTau181 > median to identify patients more likely to have AD (\"H\", > 6.74 pg/mL, n = 34). Cohen\'s d (d) of≥0.2 defined potential clinical significance.
UNASSIGNED: In the placebo group, H patients showed greater clinical progression compared to L patients (pTau181≤median) on ADCOMS (d = 0.55, p < 0.001), CDR-SB (d = 0.63, p < 0.001), MMSE (d = 0.52, p = 0.12), and ADAS-Cog14 (d = 0.53, p = 0.19). In H patients, a potentially clinically meaningful Xanamem treatment effect compared to placebo was seen in the CDR-SB (LS mean difference 0.6 units, d = 0.41, p = 0.09) and Neuropsychological Test Battery (NTB; LS mean difference 1.8 units, d = 0.26, p = 0.48) but not ADCOMS or ADAS-Cog14.
UNASSIGNED: This trial demonstrates that elevated plasma pTau181 identifies participants more likely to have progressive AD and is a suitable method for enrichment in AD clinical trials. Xanamem treatment showed evidence of potential clinically meaningful benefits.

Bone marrow adipose tissue (BMAT) comprises >10% of total adipose mass in healthy humans. It increases in diverse conditions, including ageing, obesity, osteoporosis, glucocorticoid therapy, and notably, during caloric restriction (CR). BMAT potentially influences skeletal, metabolic, and immune functions, but the mechanisms of BMAT expansion remain poorly understood. Our hypothesis is that, during CR, excessive glucocorticoid activity drives BMAT expansion. The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies glucocorticoid activity by catalysing intracellular regeneration of active glucocorticoids from inert 11-keto forms. Mice lacking 11β-HSD1 resist metabolic dysregulation and bone loss during exogenous glucocorticoid excess; thus, we hypothesised that 11β-HSD1 knockout mice would also resist excessive glucocorticoid action during CR, thereby restrining BMAT expansion and bone loss. To test this, we first confirmed that 11β-HSD1 is expressed in mouse and human bone marrow. We then investigated the effects of CR in male and female control and 11β-HSD1 knockout mice from 9 to 15 weeks of age. CR increased Hsd11b1 mRNA in adipose tissue and bone marrow. Deletion of Hsd11b1 did not alter bone or BMAT characteristics in mice fed a control diet and had little effect on tibial bone microarchitecture during CR. Notably, Hsd11b1 deletion attenuated the CR-induced increases in BMAT and prevented increases in bone marrow corticosterone in males but not females. This was not associated with suppression of glucocorticoid target genes in bone marrow. Instead, knockout males had increased progesterone in plasma and bone marrow. Together, our findings show that knockout of 11β-HSD1 prevents CR-induced BMAT expansion in a sex-specific manner and highlights progesterone as a potential new regulator of bone marrow adiposity.

The similarity of the clinical picture of metabolic syndrome and hypercortisolemia supports the hypothesis that obesity may be associated with impaired expression of genes related to cortisol action and metabolism in adipose tissue. The expression of genes encoding the glucocorticoid receptor alpha (GR), cortisol metabolizing enzymes (HSD11B1, HSD11B2, H6PDH), and adipokines, as well as selected microRNAs, was measured by real-time PCR in adipose tissue from 75 patients with obesity, 19 patients following metabolic surgery, and 25 normal-weight subjects. Cortisol levels were analyzed by LC-MS/MS in 30 pairs of tissues. The mRNA levels of all genes studied were significantly (p < 0.05) decreased in the visceral adipose tissue (VAT) of patients with obesity and normalized by weight loss. In the subcutaneous adipose tissue (SAT), GR and HSD11B2 were affected by this phenomenon. Negative correlations were observed between the mRNA levels of the investigated genes and selected miRNAs (hsa-miR-142-3p, hsa-miR-561, and hsa-miR-579). However, the observed changes did not translate into differences in tissue cortisol concentrations, although levels of this hormone in the SAT of patients with obesity correlated negatively with mRNA levels for adiponectin. In conclusion, although the expression of genes related to cortisol action and metabolism in adipose tissue is altered in obesity and miRNAs may be involved in this process, these changes do not affect tissue cortisol concentrations.

OBJECTIVE: To summarize published data on the association between glucocorticoids and metabolic dysfunction-associated steatotic liver disease (MASLD), focusing on the possible pathophysiological links and related treatment considerations.
RESULTS: Glucocorticoids, commonly used for managing many inflammatory and autoimmune diseases, may contribute to the development and progression of MASLD. Glucocorticoids may induce hyperglycemia and hyperinsulinemia, thus increasing systemic and hepatic insulin resistance, a hallmark of MASLD pathogenesis. Furthermore, glucocorticoids increase adipose tissue lipolysis, and hepatic de novo lipogenesis and decrease hepatic fatty acid β-oxidation, thus promoting MASLD development. Preclinical evidence also suggests that glucocorticoids may adversely affect hepatic inflammation and fibrosis. 11beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and 5α-reductase are implicated in the link between glucocorticoids and MASLD, the former enzyme increasing and the latter reducing the glucocorticoid action on the liver. Treatment considerations exist due to the pathogenic link between glucocorticoids and MASLD. Since iatrogenic hypercortisolism is common, glucocorticoids should be used at the minimum daily dose to control the subjective disease. Furthermore, the pharmacologic inhibition of 11β-HSD1 has provided favorable results in MASLD, both in preclinical studies and early MASH clinical trials. Glucocorticoids are closely linked to MASLD pathophysiology, with specific clinical and therapeutic implications.

BACKGROUND: 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regulates intracellular cortisol and its inhibition by the small molecule inhibitor, Xanamem™, may provide a disease-modifying strategy for Alzheimer\'s disease (AD). Animal models suggest a range of 30-60% enzyme inhibition may suffice to provide neuroprotection.
OBJECTIVE: To determine the regional brain occupancy of 11β-HSD1 by Xanamem™ in cognitively normal participants (CN) and mild cognitive impairment (MCI)/mild AD patients to investigate potential dosing ranges for future efficacy studies.
METHODS: Seventeen MCI/AD and 23 CN were included. Regional brain time-activity curves (TAC), standardized uptake values (SUV40-60) and volume of distribution (VT) from Logan plot with image derived input function from 11C-TARACT positron emission tomography (PET) were used to assess the degree of 11β-HSD1 occupancy by increasing doses of Xanamem™ (5 mg, 10 mg, 20 mg or 30 mg daily for 7 days).
RESULTS: All measures showed high 11β-HSD1 occupancy with Xanamem to similar degree in CN and MCI/AD. The dose-response relationship was relatively flat above 5 mg. Respective median (interquartile range [Q1-Q3]) 11β-HSD1 occupancy in the MCI/AD and CN groups after treatment with 10 mg Xanamem were 80% [79-81%] and 75% [71-76%] in the neocortex, 69% [64-70%] and 61% [52-63%] in the medial temporal lobe, 80% [79-80%] and 73% [68-73%] in the basal ganglia, and 71% [67-75%] and 66% [62-68%] in the cerebellum.
CONCLUSIONS: TAC, SUV40-60, and VT measures indicate Xanamem achieves high target occupancy levels with near saturation at 10 mg daily. These data support exploration of doses of≤10 mg daily in future clinical studies.

Although immune-based therapies have revolutionized the management of cancer, novel approaches are urgently needed to improve their outcome. We investigated the role of endogenous steroids in the resistance to cancer immunotherapy, as these have strong immunomodulatory functions. Using a publicly available database, we found that the intratumoral expression of 11 beta-hydroxysteroid dehydrogenase type 1 (HSD11B1), which regenerates inactive glucocorticoids into active glucocorticoids, was associated with poor clinical outcome and correlated with immunosuppressive gene signatures in patients with renal cell carcinoma (RCC). HSD11B1 was mainly expressed in tumor-infiltrating immune myeloid cells as seen by immunohistochemistry in RCC patient samples. Using peripheral blood mononuclear cells from healthy donors or immune cells isolated from the tumor of RCC patients, we showed that the pharmacological inhibition of HSD11B1 improved the response to the immune checkpoint inhibitor anti-PD-1. In a subcutaneous mouse model of renal cancer, the combination of an HSD11B1 inhibitor with anti-PD-1 treatment increased the proportion of tumor-infiltrating dendritic cells. In an intrarenal mouse tumor model, HSD11B1 inhibition increased the survival of mice treated with anti-PD-1. In addition, inhibition of HSD11B1 sensitized renal tumors in mice to immunotherapy with resiquimod, a Toll-like receptor 7 agonist. Mechanistically, we demonstrated that HSD11B1 inhibition combined with resiquimod increased T cell-mediated cytotoxicity to tumor cells by stimulating the antigen-presenting capacity of dendritic cells. In conclusion, these results support the use of HSD11B1 inhibitors to improve the outcome of immunotherapy in renal cancer and highlight the role of the endogenous glucocorticoid metabolism in the efficacy of immunotherapy.

Disturbance of sleep homeostasis encompasses health issues, including metabolic disorders like obesity, diabetes, and augmented stress vulnerability. Sleep and stress interact bidirectionally to influence the central nervous system and metabolism. Murine models demonstrate that decreased sleep time is associated with an increased systemic stress response, characterized by endocrinal imbalance, including the elevated activity of hypothalamic-pituitary-adrenal axis, augmented insulin, and reduced adiponectin, affecting peripheral organs physiology, mainly the white adipose tissue (WAT). Within peripheral organs, a local stress response can also be activated by promoting the formation of corticosterone. This local amplifying glucocorticoid signaling is favored through the activation of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). In WAT, 11β-HSD1 activity is upregulated by the sympathetic nervous system, suggesting a link between sleep loss, augmented stress response, and a potential WAT metabolic disturbance. To gain more understanding about this relationship, metabolic and stress responses of WAT-sympathectomized rats were analyzed to identify the contribution of the autonomic nervous system to stress response-related metabolic disorders during chronic sleep restriction. Male Wistar rats under sleep restriction were allowed just 6 h of daily sleep over eight weeks. Results showed that rats under sleep restriction presented higher serum corticosterone, increased adipose tissue 11β-HSD1 activity, weight loss, decreased visceral fat, augmented adiponectin, lower leptin levels, glucose tolerance impairment, and mildly decreased daily body temperature. In contrast, sympathectomized rats under sleep restriction exhibited decreased stress response (lower serum corticosterone and 11β-HSD1 activity). In addition, they maintained weight loss, explained by a reduced visceral fat pad, leptin, and adiponectin, improved glucose management, and persisting decline in body temperature. These results suggest autonomic nervous system is partially responsible for the WAT-exacerbated stress response and its metabolic and physiological disturbances.

BACKGROUND: Glucocorticoids play a significant role in metabolic processes and pathways that impact muscle size, mass, and function. The expression of 11-beta-hydroxysteroid dehydrogenase type 1 (HSD11B1) has been previously described as a major regulator of skeletal muscle function in glucocorticoid-induced muscle atrophy and aging humans. Our study aimed to investigate glucocorticoid metabolism, including the expression of HSD11B1 in skeletal muscle, in patients with sarcopenia.
METHODS: Muscle biopsies were taken from the vastus lateralis muscle of thirty-three patients over 60 years of age with hip fractures. Sarcopenia status was assessed according to the criteria of the European Working Group on Sarcopenia in Older People 2. Skeletal muscle mass was measured by bioelectrical impedance analysis. Cortisol and cortisone concentrations were measured in serum. Gene expression analysis of HSD11B1, NR3C1, FBXO32, and TRIM63 in muscle biopsies was performed. Serial cross sections of skeletal muscle were labeled with myosin heavy chain slow (fiber type-1) and fast (fiber type-2) antibodies.
RESULTS: The study included 33 patients (21 women) with a mean age of 82.5 ± 6.3 years, 17 patients revealed sarcopenic (n = 16 non-sarcopenic). Serum cortisone concentrations were negatively correlated with muscle mass (ß =  - 0.425; p = 0.034) and type-2 fiber diameter (ß =  - 0.591; p = 0.003). Gene expression of HSD11B1 (ß =  - 0.673; p = 0.008) showed a negative correlation with muscle mass in the sarcopenic group. A significant correlation was found for the non-sarcopenic group for NR3C1 (ß = 0.548; p = 0.028) and muscle mass.
CONCLUSIONS: These findings suggest a pathogenetic role of HSD11B1 in sarcopenic muscle.

Extra-adrenal glucocorticoid (GC) synthesis at epithelial barriers, such as skin and intestine, has been shown to be important in the local regulation of inflammation. However, the role of local GC synthesis in the lung is less well studied. Based on previous studies and the uncontentious efficacy of corticosteroid therapy in asthma patients, we here investigated the role of 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1/Hsd11b1)-dependent local GC reactivation in the regulation of allergic airway inflammation.
Airway inflammation in Hsd11b1-deficient and C57BL/6 wild type mice was analyzed after injection of lipopolysaccharide (LPS) and anti-CD3 antibody, and in acute and chronic models of airway hypersensitivity induced by house dust mite (HDM) extract. The role of 11β-HSD1 in normal and inflammatory conditions was assessed by high dimensional flow cytometry, histological staining, RT-qPCR analysis, ex vivo tissue cultures, GC-bioassays and protein detection by ELISA and immunoblotting.
Here we show that lung tissue from Hsd11b1-deficient mice synthesized significantly less GC ex vivo compared with wild type animals in response to immune cell stimulation. We further observed a drastically aggravated phenotype in Hsd11b1-deficient mice treated with HDM extract compared to wild type animals. Besides eosinophilic infiltration, Hsd11b1-deficient mice exhibited aggravated neutrophilic infiltration caused by a strong Th17-type immune response.
We propose an important role of 11β-HSD1 and local GC in regulating Th17-type rather than Th2-type immune responses in HDM-induced airway hypersensitivity in mice by potentially controlling Toll-like receptor 4 (TLR4) signaling and cytokine/chemokine secretion by airway epithelial cells.