Glucocorticoid Concentrations Research Articles

Activation of Local 11β-Hydroxysteroid Dehydrogenase Type 1 by Diosmetin Enhances Endogenous Glucocorticoid Levels to Alleviate Skin Inflammation: Insights Into a Novel Therapeutic Strategy for Atopic Dermatitis.

Glucocorticoids (GCs) are synthesised de novo by peripheral tissues and the adrenal cortex of the hypothalamic-pituitary-adrenal axis. Skin expresses an enzyme called 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which reduces cortisone to the active hormone cortisol which activates GC receptors. 11β-HSD1 plays a significant role in alleviating atopic inflammation through the elevation of the concentrations of active GC in the skin. This study aimed to investigate the role of diosmetin as an activator of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). In human keratinocytes, diosmetin was found to upregulate 11β-HSD1 protein expression and cortisol levels, as well as the transcriptional expression of 11β-HSD1 mRNA. However, this upregulation of 11β-HSD1 mRNA was abrogated in keratinocytes transfected with 11β-HSD1 small interfering RNA (siRNA). In an atopic dermatitis (AD) murine model, topical administration of diosmetin significantly attenuated basal transepidermal water loss (TEWL) and the Eczema Area and Severity Index (EASI), while enhancing stratum corneum (SC) hydration. Diosmetin also increased corticosterone levels in the SC and upregulated 11β-HSD1 expression in both the serum and epidermis. Furthermore, diosmetin treatment led to a marked reduction in serum immunoglobulin E (IgE) and tumour necrosis factor-α (TNF-α) levels, and suppressed mRNA expression of thymic stromal lymphopoietin (TSLP), interleukin-1β (IL-1β), IL-4, and IL-13 in the epidermis. Collectively, these findings suggest that diosmetin promotes the endogenous activation of glucocorticoids via local 11β-HSD1 activation, underscoring its potential as a novel topical therapeutic agent for the management of inflammatory skin disorders, such as AD.

Effect of exogenous manipulation of glucocorticoid concentrations on meerkat heart rate, behaviour and vocal production.

Encoding of emotional arousal in vocalisations is commonly observed in the animal kingdom, and provides a rapid means of information transfer about an individual's affective responses to internal and external stimuli. As a result, assessing affective arousal-related variation in the acoustic structure of vocalisations can provide insight into how animals perceive both internal and external stimuli, and how this is, in turn, communicated to con- or heterospecifics. However, the underlying physiological mechanisms driving arousal-related acoustic variation remains unclear. One potential driver of such variation in behaviour and vocal production are glucocorticoids. Through exogenous glucocorticoid manipulation, we aimed to gain insight on the relationship between arousal and physiological parameters, behaviour and vocal production in wild meerkats (Suricata suricatta). To this aim, we administered glucocorticoids to wild meerkats, and recorded their heart rate, vigilance behaviour, call rate and acoustic structure during natural behavioural contexts. The results suggest that, although the glucocorticoid treatment did increase plasma glucocorticoid levels, this did not result in observable changes in heart rate, vigilance, or vocal production. This lack of treatment effect suggests that, while glucocorticoids may be a significant component and correlate of the arousal response, they are not the direct drivers of affective arousal related changes in heart rate, behaviour, or vocal production.

Adverse Cardiovascular Risk Profile and Increased Diurnal Salivary Cortisol in Girls With Turner Syndrome: An Exploratory Study.

Patients with Turner Syndrome (TS) and those exposed to high concentrations of glucocorticoids have a number of characteristics in common, including an increased risk of cardiovascular disease. Pediatric TS patients underwent studies of salivary cortisol (SC) and cortisone (SCn), body composition, continuous glucose monitoring, vascular function, and ambulatory blood pressure (BP). Biochemical indicators of cardiovascular risk were also measured. Data were compared to matched healthy controls (HCs) or interpreted according to reference populations. Ten patients, aged 14.1 ± 2.3 years participated. Mean SC was higher in girls with TS, although the early morning measurement was lower resulting in a flatter diurnal profile. Body mass index was > 1.0 SDS in five and muscle-to-fat ratio was low (< 0.8) in six participants. Four had proatherogenic lipid profiles and six had raised clotting and/or inflammatory markers. Mean glucose concentration was higher in TS than in HCs (109.8 vs. 102.6 mg/dL, p = 0.003). Loss of nocturnal dipping in BP was universal, and hypertension was present in three patients. TS participants had an adverse cardiovascular profile. The same cohort also exhibited increased cortisol exposure and the clinical significance of these dual findings warrants further investigation.

Energetic costs of social dominance in wild male baboons.

In vertebrates, glucocorticoids can be upregulated in response to both psychosocial and energetic stressors, making it difficult to identify the cause of elevated glucocorticoid concentrations when both types of stressors are present. This problem has been particularly challenging in studies of social dominance rank in wild animals. In contrast to glucocorticoids, thyroid hormone concentrations are largely unaffected by psychosocial stressors and therefore offer a better estimate of energetic challenges. Here, we measured faecal metabolites of both triiodothyronine (mT3) and glucocorticoids (fGC) in wild baboons and assessed how these hormonal profiles vary with male dominance rank. We found that alpha males have lower mT3 and higher fGC than males of other ranks, indicating sustained energetic costs of alpha status. By contrast, low-ranking males have higher mT3 but similar fGC concentrations than non-alpha high-ranking males, reflecting their lower exposure to energetic stressors but greater vulnerability to psychosocial stressors than higher-ranking males. We also found that mate-guarding of fertile females, a behaviour expressed at higher rates by alpha males, partly explains the energetic costs of high social status. These findings offer evidence of the different types of costs experienced by low- and high-ranking animals.

Associations of Maternal Salivary Cortisol and Psychological Symptoms With Human Milk's Microbiome Composition.

Human milk (HM) is considered the best source of infant nutrition with many benefits for the infant. However, pregnancy changes can lead to increased stress in some women, which might affect HM composition. Although studies have demonstrated a link between maternal psychopathology and child development, it remains unclear how maternal psychobiological changes can be intergenerationally transmitted. We aimed to investigate the associations of maternal stress, depressive symptoms, and anxiety symptoms with the HM microbiome; to analyze these parameters in relation to HM glucocorticoid concentrations; and to explore the influence of HM glucocorticoids on HM bacterial composition. One hundred women completed psychological questionnaires (e.g., EPDS, STAI, GAS) at 34-36 weeks' gestation and in the early postpartum period and provided saliva at 34-36 and 38 weeks' gestation. HM samples were collected in the early postpartum. Microbiota were analyzed using 16S rRNA amplicon sequencing. Birth anxiety was negatively correlated with Alphaproteobacteria (τ = -0.20, FDR = 0.01), whereas in the postpartum period, anxiety symptoms were negatively correlated with different taxa. The sum of postpartum-related symptoms was linked to lower Propionibacteriales. Salivary cortisol AUCg at 34-36 weeks was negatively correlated with Stenotrophomonas (τ = -0.24, FDR = 0.05), whereas HM cortisol was positively correlated with Streptococcus mitis (τ = 0.26, FDR = 0.03) and Gemella haemolysans (τ = 0.24, FDR = 0.02). No associations emerged between psychobiological parameters and HM glucocorticoids. Higher perinatal psychological symptoms and prenatal salivary cortisol AUCg were associated with lower relative abundances of different bacteria, whereas higher HM cortisol was linked to higher Gemella and Streptococcus. These findings suggest a negative association between high maternal psychobiological symptoms and relative abundances of the milk microbiota.

Prepartal stress, prepartal and postpartal hair glucocorticoid concentrations, and symptoms of postpartum depression three days and 12 weeks after delivery

Prepartal stress, prepartal and postpartal hair glucocorticoid concentrations, and symptoms of postpartum depression three days and 12 weeks after delivery

Ornamentation and body condition, but not glucocorticoids, predict wild songbird cloacal microbiome community and diversity

Animal populations can exhibit dramatic variation in individual fitness, and microbiota are emerging as a potentially understudied factor influencing host health. Bacterial diversity and community structure of the gut microbiome are associated with many aspects of fitness in animals, but relatively little is known about the generality of these relationships in wild populations and non‐mammalian taxa. We studied the northern cardinal Cardinalis cardinalis, a member of a taxon that is ecologically important but underrepresented in microbiome research: songbirds. To test for relationships between the microbiota and host fitness, we sampled the cloacal microbiomes of wild cardinals and measured body condition index, assessed coloration of sexual ornaments (beak and plumage), and collected blood to estimate the glucocorticoid response to stress. Both alpha and beta bacterial diversity were related to individual variation in body condition and several sexual ornaments, but not glucocorticoid concentrations. Our results from a free‐living songbird population add to a growing body of research linking avian host fitness to internal bacterial community characteristics. This study sets the stage for manipulative experiments to determine how challenges to fitness and microbiomes may upset these relationships.

Impaired 11β-hydroxysteroid dehydrogenase type 2 activity in kidney disease disrupts 11-oxygenated androgen biosynthesis.

11-oxygenated androgens are a group of adrenal-derived steroids that require peripheral activation. In vitro data highlight a putative role for 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) in 11-oxygenated androgen biosynthesis, converting 11β-hydroxyandrostenedione (11OHA4) to 11-ketoandrostenedione (11KA4), the direct precursor of the potent androgen 11-ketotestosterone (11KT). As the kidney is the major site of HSD11B2 expression, we hypothesized that patients with chronic kidney disease (CKD) would have reduced 11-oxygenated androgen biosynthesis due to impaired HSD11B2 activity. To determine the role of HSD11B2 in 11-oxygenated androgen biosynthesis using a human CKD cohort alongside complementary cell culture and computational modeling approaches. Cross-sectional observational study of patients with CKD (n=85) and healthy controls (n=46) measuring serum and urinary concentrations of glucocorticoids, classic and 11-oxygenated androgens by liquid chromatography-tandem mass spectrometry. A computational model of peripheral 11-oxygenated androgen biosynthesis was fitted to the serum data to calculate relative HSD11B2 expression levels for each participant. HSD11B2 activity declined with eGFR, evidenced by higher cortisol (F)/cortisone (E) ratios in CKD patients compared to controls (p<0.0001). Serum concentrations of E, 11KA4, 11KT and 11β-hydroxytestosterone were lower in patients with CKD compared to controls (p<0.0001 for each). A computational model based on enzyme kinetic parameters of HSD11B2, 11β-hydroxysteroid dehydrogenase type 1, 17β-hydroxysteroid dehydrogenase type 2 and aldo-keto reductase 1C3 confirmed HSD11B2 as the key enzyme responsible for reduced 11-oxygenated androgen biosynthesis in CKD. Predicted HSD11B2 expression correlated with eGFR. This is the first in vivo study to confirm a central role for renal HSD11B2 in 11-oxygenated androgen biosynthesis. Determining the clinical implications of this observation for patients with CKD requires further research.

7662 Mass Spectrometry Imaging Reveals Region-, Age-, And Sex-Specific Effects Of Lipopolysaccharide Administration On Glucocorticoids In Mouse Lymphoid Organs

Abstract Disclosure: M. Salehzadeh: None. S. Khan: None. R. Andrew: None. K.K. Soma: None. Glucocorticoids (GCs) are steroids that are critical for immune function. Immune organs, such as the thymus and spleen, locally produce GCs (i.e., immunosteroids). However, GC concentrations in the thymus and spleen at the cellular level, and how these levels are affected by stress, remain largely unknown. We used state-of-the-art mass spectrometry imaging (MSI) to elucidate the spatial distribution of GCs in the neonatal and adult mouse thymus and spleen 1) at baseline and 2) after an acute stressor. We used MSI to measure 11-deoxycorticosterone (DOC), corticosterone, and 11-dehydrocorticosterone (DHC) in different regions of the thymus (medulla/cortex) and spleen (white/red pulp) after an immunological challenge. We administered lipopolysaccharide (LPS; i.p.) at low (50μg/kg) and high (400μg/kg) doses or saline (vehicle) to male and female C57BL/6J mice at post-natal day (PND) 5 (neonatal) and 90 (adult) (n=6/sex/group/age). 4hr after treatment, we collected thymus and spleen on liquid nitrogen. Cryosections (10μm) were subject to MSI following Girard-T reagent derivatization and α-cyano-4-hydroxycinnamic acid matrix application. Matrix assisted laser desorption/ionisation (MALDI) was used for sampling, coupled to Fourier-transform ion cyclotron mass spectrometry (100μm resolution; positive mode; Bruker 12T SolariX). Adjacent sections were taken to determine histological zones by H&amp;E staining. Preliminary results indicate that LPS increased DOC, corticosterone, and DHC levels by 2- to 9-fold in lymphoid organs at both ages. There was a dose-dependent increase in thymus and spleen GC levels at PND5, but not PND90. At PND5, GC levels were similarly distributed across each tissue in both sexes. In contrast, at PND90, thymic corticosterone levels were greater in males than females in the medulla and cortex. Interestingly, in PND90 thymus, the medulla had greater DHC levels than the cortex only after LPS treatments. In PND90 spleen, GC levels significantly increased after LPS, yet there was no significant difference in GC distribution between sexes or red and white pulp. These results suggest that GC production is uniform across neonatal lymphoid organs. However, in adulthood, the thymus exhibits region-specific GC metabolism. Our results expand knowledge of steroid intracrinology in thymus and spleen and potential effects of environmental stressors (e.g., infectious diseases, toxins) on immune GC responses. Further, our novel MSI method for GC detection in murine lymphoid organs can help inform future techniques in pharmacokinetics for localized thymic and splenic targeting of steroids and steroid modulators. Presentation: 6/3/2024

The effect of stress on liver function

«Psychosocial stress» is becoming an increasingly common concept in today’s complex and highly demanding society. Although the liver is one of the body’s most resilient organs, it is still vulnerable to the damaging effects of stress and aging, leading to liver disease, severe scarring and impaired function. Mental stress increases mortality from liver disease. Stressors activate macrophages and trigger an innate immune response, which then leads to the induction of inflammation and liver damage. In its diseases, symptoms such as low energy, fatigue, changes in employment status and functionality can also lead to the development of depression. The various physiological effects of glucocorticoids and catecholamines released into the bloodstream during stress lead to inflammation and oxidative stress in the liver. Research has explained the complex interactions that occur between stress system effectors and inflammation. Chronic psychological stress leads to an increase in serum glucocorticoid concentrations and the release of catecholamines, which increases the need for insulin. Insulin resistance leads to the development of metabolic-associated steatotic liver disease. The high prevalence of hepatogenic fatigue in chronic diffuse liver disease, its negative impact on the quality of life of patients, and the lack of effect of basic treatment lead to its aggravation due to stress. Sublingual S-adenosyl-L-methionine is effective in the treatment of hepatogenic stress fatigue, both in short-term and long-term use as part of the complex therapy of liver diseases.

Ectoin attenuates cortisone-induced skin issues by suppression GR signaling and the UVB-induced overexpression of 11β-HSD1.

Accelerated pace of modern work and lifestyles subject individuals to various external and psychological stressors, which, in turn, can trigger additional stress through visible signs of fatigue, hair loss, and obesity. As the primary stress hormone affecting skin health, cortisol connects to the glucocorticoid receptor (GR) to aggravate skin issues induced by stress. This activation depends on the expression of 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) in skin cells, which locally converts cortisone-produced by the central and peripheral hypothalamic-pituitary-adrenal axis-into its active form. Our study delves deeper into stress's adverse effects on the skin, including the disruption of keratinocyte structural proteins, the loss of basement membrane proteins, and the degradation of collagen. Remarkably, we discovered that Ectoin, an amino acid derivative obtained from halophilic bacteria, is capable of mitigating the inhibitory impacts of cortisone on the expression of cutaneous functional proteins, including involucrin, loricrin, laminin-5, and claudin-1. Moreover, Ectoin reduces the suppressive effect of stress on collagen and hyaluronic acid synthesis by impeding GR signal transduction. Additionally, Ectoin counterbalances the UVB-induced overexpression of 11β-HSD1, thereby diminishing the concentration of endogenous glucocorticoids. Our findings illuminate the significant potential of Ectoin as a preventative agent against stress-induced skin maladies.

Fast and reliable quantification of aldosterone, cortisol and cortisone via LC-MS/MS to study 11β-hydroxysteroid dehydrogenase activities in primary cell cultures

Cell culture experiments can support characterization of enzymatic activities in healthy and tumorous human tissues. Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) enables simultaneous measurement of several steroids from a single sample, facilitating analysis of molecular pathways involved in steroid biosynthesis. We developed a reliable but fast method for quantification of cortisol, cortisone and aldosterone in cell culture supernatant. Validation, including investigation of matrix-matched calibration, was performed for two different cell types. Utility of the method was demonstrated in the study of 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) activity under conditions of glucocorticoid and mineralocorticoid excess in different cell types. Aldosterone, cortisol and cortisone were extracted by liquid-liquid extraction (LLE) with methyl tert-butyl ether from 1 mL of cell culture supernatant. Steroids were separated on a Kinetex biphenyl column (50 ×2.1 mm, 2.6 µm) with gradient elution of water and methanol containing 2 mM ammonium format and analysed in multiple reaction monitoring mode after positive electrospray ionization. Application of the method included cell culture experiments with two different primary cell types, human coronary artery smooth muscle cells (HCSMC) and human coronary artery endothelial cells (EC). Cells were treated with different concentrations of cortisol, aldosterone and mifepristone, a glucocorticoid receptor antagonist and quantitative PCR was performed. The method exhibits high precision (CV ≤ 6 %) and accuracy (deviation from nominal concentration ≤ 6 %) for concentrations above the limit of quantification (LoQ) which is 0.11, 0.56 and 0.69 nmol/L for aldosterone, cortisone and cortisol, respectively. Calibration curves did not differ when prepared in media or solvent. The method enabled us to confirm activity of HSD11B2 and concentration dependent conversion of cortisol to cortisone in HCSMC (median conversion ratio at 140 nM cortisol = 1.46 %). In contrast we did not observe any HSD11B2 activity in EC. Neither addition of high aldosterone, nor addition of 1 µM mifepristone had impact on glucocorticoid concentrations. Quantitative PCR revealed expression of HSD11B1 and HSD11B2 in HCSMC but not in EC. We present a fast and reliable method for quantification of cortisol, cortisone and aldosterone in cell culture supernatants. The method enabled us to study HSD11B2 activity in two different cell types and will support future experiments investigating mechanisms of target organ damage in conditions of glucocorticoid and mineralocorticoid excess.

Hair glucocorticoid levels decrease after multimodal inpatient treatment and predict therapy outcome in burnout-related depressive disorders

Objectives Hair cortisol concentration (HCC) indicates chronic stress exposure, which is a risk factor in the pathogenesis of burnout and depression. However, findings on HCC are inconsistent. Similarly, intervention studies show mixed effects on HCC. The present study aimed to shed light on these inconsistencies, by additionally considering also hair cortisone. Methods Twenty-five patients with a burnout-related depressive disorder receiving a multimodal inpatient treatment for clinical burnout and 17 matched healthy controls participated in this study. All participants provided 1 cm long hair samples at the beginning and end of the treatment. HCC and hair cortisone levels (HCNC) were determined. Meteorological data and duration of sick leave were considered as potential covariates. Burnout and depression were assessed with self-ratings, the latter also with examiner ratings. Results There were no significant group differences in glucocorticoid levels. Treatment led to a decrease in both depression severity and hair glucocorticoid concentration in inpatients, while lower HCNC in particular predicted a greater reduction in depression severity. Moreover, meteorological data and the duration of sick leave were also found to have an effect on hair glucocorticoid concentrations. Conclusions These results suggest that multimodal inpatient treatment of clinical burnout considerably reduced stress on both a psychological and biological level. In parallel, hair glucocorticoids appear to be sensitive biomarkers for the evaluation of treatment success and prediction. Examining both HCC and HCNC in intervention studies may provide clearer results than the usual examination of HCC alone.

IMPACT OF STRESS ON EMOTIONAL HEALTH AND COGNITIVE FUNCTION

Background. Emotional stress can have both a positive effect, which is aimed at adaptation, and a negative one, which affects the higher integrative functions of the brain, and also leads to the development of numerous diseases. In this regard, the problem of establishing the influence of stress factors on the emotional state and cognitive function becomes relevant, which creates the prerequisites for a detailed analysis of the scientific data. Aim: to investigate the impact of chronic stress on emotional health and to determine the impact of stressful factors on human cognitive functions. Material and methods. The review included 63 articles, which have been selected using the following keywords: «chronic stress», «cortisol», «cognitive functions», «emotions», «memory», in the databases of scientific medical data PubMed, Scopus and Web of Science. An analysis of the existing research results on the impact of stress on emotional health and cognitive functions was carried out. Results. Stress causes a multiple effect on the human nervous system, leading to structural changes in different parts of the brain such as atrophy and reduction of brain volume and mass with long-term consequences for the nervous system resulting in impaired cognitive abilities and memory. Alteration of neuronal plasticity, caused by chronic stress, due to dendrite atrophy and decreased spinal density may underlie the depressive disorders. Additionally, chronic inflammation, which also results from prolonged stress, can develop depression and disturb cognitive functions. The hippocampus contains the high density of glucocorticoids receptors, thus increased basal concentration of cortisol may result in functional and structural changes in the hippocampus with atrophy and impaired neurogenesis. Chronic stress can affect cognitive function both acutely and chronically. The acute effect is caused by beta-adrenergic effects, while the chronic effect is caused by long-term changes in gene expression mediated by steroid hormones. Conclusion. Chronic stress with an increased basal concentration of glucocorticoids affects the hippocampus leading to impaired memory, cognition, and thinking, also increases risk of depression, anxiety disorders.

Endogenous serum glucocorticoid concentrations, steroidogenic enzyme activity, and 90-day mortality in patients hospitalized with COVID-19: an observational cohort study.

In the context of severe coronavirus disease 2019 (COVID-19) illness, we examined endogenous glucocorticoid concentrations, steroidogenic enzyme activity, and their correlation with inflammation and patient outcomes. This observational study included 125 hospitalized COVID-19 patients and 101 healthy individuals as a reference group. We utilized LC-MS to assess serum concentrations of 11-deoxycortisol, cortisol, and cortisone, as well as activities of steroidogenic enzymes (11β-hydroxylase and 11β-hydroxysteroid-dehydrogenase type 1). Cox proportional hazards regression analysis and competing risk analysis were employed to analyze associations between glucocorticoid concentrations and outcomes, adjusting for relevant factors. In patients with COVID-19, cortisol concentrations were higher and cortisone concentrations were lower compared to the reference group, while 11-deoxycortisol concentrations were similar. Steroidogenic enzyme activity favored cortisol production. Correlations between glucocorticoid concentrations and inflammatory markers were low. A doubling in concentrations cortisol, was associated with increased 90-day mortality and mechanical ventilation (HR: 2.40 95% CI: (1.03-5.59) , P = 0.042 and HR: 3.83 (1.19-12.31), P = 0.024). A doubling in concentrations of 11-deoxycortisol was also associated to mortality (HR: 1.32 (1.05-1.67), P = 0.018), whereas concentrations of cortisone were associated with mechanical ventilation (HR: 5.09 (1.49-17.40), P = 0.009). In conclusion, serum concentrations of glucocorticoid metabolites were altered in patients hospitalized with severe COVID-19, and steroidogenic enzyme activity resulting in the conversion of cortisone to biologically active cortisol was preserved, thus not favoring critical-illness-related corticosteroid insufficiency at the enzymatic level. Glucocorticoid release did not counterbalance the hyperinflammatory state in patients with severe COVID-19. High serum concentrations of 11-deoxycortisol and cortisol were associated with 90-day mortality, and high serum concentrations of cortisol and cortisone were associated with mechanical ventilation.

Fasting reshapes tissue-specific niches to improve NK cell-mediated anti-tumor immunity

Fasting is associated with improved outcomes in cancer. Here, we investigated the impact of fasting on natural killer (NK) cell anti-tumor immunity. Cyclic fasting improved immunity against solid and metastatic tumors in an NK cell-dependent manner. During fasting, NK cells underwent redistribution from peripheral tissues to the bone marrow (BM). In humans, fasting also reduced circulating NK cell numbers. NK cells in the spleen of fasted mice were metabolically rewired by elevated concentrations of fatty acids and glucocorticoids, augmenting fatty acid metabolism via increased expression of the enzyme CPT1A, and Cpt1a deletion impaired NK cell survival and function in this setting. In parallel, redistribution of NK cells to the BM during fasting required the trafficking mediators S1PR5 and CXCR4. These cells were primed by an increased pool of interleukin (IL)-12-expressing BM myeloid cells, which improved IFN-γ production. Our findings identify a link between dietary restriction and optimized innate immune responses, with the potential to enhance immunotherapy strategies.

ATP-binding cassette family C member 1 constrains metabolic responses to high-fat diet in male mice.

Glucocorticoids modulate glucose homeostasis, acting on metabolically active tissues such as liver, skeletal muscle, and adipose tissue. Intracellular regulation of glucocorticoid action in adipose tissue impacts metabolic responses to obesity. ATP-binding cassette family C member 1 (ABCC1) is a transmembrane glucocorticoid transporter known to limit the accumulation of exogenously administered corticosterone in adipose tissue. However, the role of ABCC1 in the regulation of endogenous glucocorticoid action and its impact on fuel metabolism has not been studied. Here, we investigate the impact of Abcc1 deficiency on glucocorticoid action and high-fat-diet (HFD)-induced obesity. In lean male mice, deficiency of Abcc1 increased endogenous corticosterone levels in skeletal muscle and adipose tissue but did not impact insulin sensitivity. In contrast, Abcc1-deficient male mice on HFD displayed impaired glucose and insulin tolerance, and fasting hyperinsulinaemia, without alterations in tissue corticosterone levels. Proteomics and bulk RNA sequencing revealed that Abcc1 deficiency amplified the transcriptional response to an obesogenic diet in adipose tissue but not in skeletal muscle. Moreover, Abcc1 deficiency impairs key signalling pathways related to glucose metabolism in both skeletal muscle and adipose tissue, in particular those related to OXPHOS machinery and Glut4. Together, our results highlight a role for ABCC1 in regulating glucose homeostasis, demonstrating diet-dependent effects that are not associated with altered tissue glucocorticoid concentrations.

Traffic Noise Impacts Glucocorticoid Response, Activity, and Growth in Two Species of Tadpoles.

There is a large body of evidence linking increased noise to negative health effects for animals. Anthropogenic noise induces behavioral and physiological reactions across a range of taxa and increased traffic noise affects glucocorticoid (GC) hormones associated with the stress response in amphibians. GCs help to maintain homeostasis while balancing energetic trade-offs between reproduction, growth, and activity. Stressors during early development can impact fitness at later life stages. We measured growth, activity, and GCs in response to high levels of traffic noise in two tadpole species that differ in life history: Acris crepitans and Rana berlandieri. We predicted that earlier exposures to traffic noise will slow down the development and alter the behavior and GC concentrations differently than later exposures. Subjects were initially either exposed to natural levels of traffic noise for 8 days (early exposure) or a white noise control (later exposure), then the treatment was switched. Activity was measured via focal sampling and tadpoles were categorized as active if movement was detected. Tadpoles exposed to white noise initially maintained mass and activity throughout the experiment and early exposure to traffic noise had a greater impact on mass, activity, and GCs. Tadpoles exposed to traffic noise initially lost mass, with A. crepitans regaining mass but not R. berlandieri. When exposed earlier to traffic noise, R. berlandieri increased movement when shifted to the white noise treatment while A. crepitans did not significantly change activity. Acris creptians had higher corticosterone release rates compared to R. berlandieri, and in both species, release rates were higher for tadpoles exposed to noise earlier. The longer-lived R. berlandieri allocated more of their energetic resources into activity, while the shorter-lived A. crepitans allocated energy toward growth. Rana berlandieri and A. crepitans utilized different coping strategies to contend with early exposure to traffic noise, potentially due to differences in life histories. Our findings suggest that these tadpoles employ different coping mechanisms to modulate stress responses in noise-polluted environments, and these mechanisms could influence their fitness later in life. Further study is needed to understand the impact in more sensitive tadpole species.

Long-term glucocorticoid infusion impairs epididymal adipocyte metabolism and maturation and affects miR-150–5p actions

The most common form of hypercortisolism is iatrogenic Cushing's syndrome. Lipodystrophy and metabolic disorders can result from the use of exogenous glucocorticoids (GC). Adipocytes play an important role in the production of circulating exosomal microRNAs, and knockdown of Dicer promotes lipodystrophy. The aim of this study is to investigate the effect of GCs on epididymal fat and to assess their influence on circulating microRNAs associated with fat turnover. The data indicate that despite the reduction in adipocyte volume due to increased lipolysis and apoptosis, there is no difference in tissue mass, suggesting that epididymal fat pad, related to animal size, is not affected by GC treatment. Although high concentrations of GC have no direct effect on epididymal microRNA-150–5p expression, GC can induce epididymal adipocyte uptake of microRNA-150–5p, which regulates transcription factor Ppar gamma during adipocyte maturation. In addition, GC treatment increased lipolysis and decreased glucose-derived lipid and glycerol incorporation. In conclusion, the similar control and GC epididymal fat mass results from increased dense fibrogenic tissue and decreased adipocyte volume induced by the lipolytic effect of GC. These findings demonstrate the complexity of epididymal fat. They also highlight how this disease alters fat distribution. This study is the first in a series published by our laboratory showing the detailed mechanism of adipocyte turnover in this disease.

Seasonal Hair Glucocorticoid Fluctuations in Wild Mice (Phyllotis darwini) within a Semi-Arid Landscape in North-Central Chile.

Mammals in drylands face environmental challenges exacerbated by climate change. Currently, human activity significantly impacts these environments, and its effects on the energy demands experienced by individuals have not yet been determined. Energy demand in organisms is managed through elevations in glucocorticoid levels, which also vary with developmental and health states. Here, we assessed how anthropization, individual characteristics, and seasonality influence hair glucocorticoid concentration in the Darwin's leaf-eared mouse (Phyllotis darwini) inhabiting two areas with contrasting anthropogenic intervention in a semi-arid ecosystem of northern Chile. Hair samples were collected (n = 199) to quantify hair corticosterone concentration (HCC) using enzyme immunoassays; additionally, sex, body condition, and ectoparasite load were recorded. There were no differences in HCC between anthropized areas and areas protected from human disturbance; however, higher concentrations were recorded in females, and seasonal fluctuations were experienced by males. The results indicate that animals inhabiting semi-arid ecosystems are differentially stressed depending on their sex. Additionally, sex and season have a greater impact on corticosterone concentration than anthropogenic perturbation, possibly including temporal factors, precipitation, and primary production. The influence of sex and seasonality on HCC in P. darwini make it necessary to include these variables in future stress assessments of this species.