The American lifestyle-induced obesity syndrome diet in male and female rodents recapitulates the clinical and transcriptomic features of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis

The pathogenesis of nonalcoholic fatty liver disease (NAFLD) and the progression to nonalcoholic steatohepatitis (NASH) and increased risk of hepatocellular carcinoma remain poorly understood. Additionally, there is increasing recognition of the extrahepatic manifestations associated with NAFLD and NASH. We demonstrate that intervention with the American lifestyle-induced obesity syndrome (ALIOS) diet in male and female mice recapitulates many of the clinical and transcriptomic features of human NAFLD and NASH. Male and female C57BL/6N mice were fed either normal chow (NC) or ALIOS from 11 to 52 wk and underwent comprehensive metabolic analysis throughout the duration of the study. From 26 wk, ALIOS-fed mice developed features of hepatic steatosis, inflammation, and fibrosis. ALIOS-fed mice also had an increased incidence of hepatic tumors at 52 wk compared with those fed NC. Hepatic transcriptomic analysis revealed alterations in multiple genes associated with inflammation and tissue repair in ALIOS-fed mice. Ingenuity Pathway Analysis confirmed dysregulation of metabolic pathways as well as those associated with liver disease and cancer. In parallel the development of a robust hepatic phenotype, ALIOS-fed mice displayed many of the extrahepatic manifestations of NAFLD, including hyperlipidemia, increased fat mass, sarcopenia, and insulin resistance. The ALIOS diet in mice recapitulates many of the clinical features of NAFLD and, therefore, represents a robust and reproducible model for investigating the pathogenesis of NAFLD and its progression.NEW & NOTEWORTHY Nonalcoholic fatty liver disease (NAFLD) affects 30% of the general population and can progress to nonalcoholic steatohepatitis (NASH) and potentially hepatocellular carcinoma. Preclinical models rely on mouse models that often display hepatic characteristics of NAFLD but rarely progress to NASH and seldom depict the multisystem effects of the disease. We have conducted comprehensive metabolic analysis of both male and female mice consuming a Western diet of trans fats and sugar, focusing on both their hepatic phenotype and extrahepatic manifestations

Albuminuria is a marker of increasing intracranial and extracranial vascular involvement in Type 2 diabetic Chinese patients

AIMS/HYPOTHESIS: Albuminuria has been reported to be a marker of cardiovascular risk factors and disease morbidity and mortality, but its relationship with intracerebral atherosclerotic disease is less clear. The aim of this study was to investigate the association between albuminuria and intracranial and extracranial vascular involvement in Chinese Type 2 diabetic patients. METHODS: The anthropometric and fasting biochemical measurements of 966 Type 2 diabetic patients with normoalbuminuria (55.6%), microalbuminuria (27.7%) or macroalbuminuria (16.7%) were compared. The prevalence of microvascular and macrovascular disease and middle cerebral artery (MCA) stenosis, measured by transcranial Doppler ultrasound, were also compared between the groups. RESULTS: Albuminuria was closely associated with a range of adverse parameters, including high BP, dyslipidaemia, smoking and adiposity (all p<0.01). The prevalence of microvascular disease (retinopathy p<0.001) and macrovascular disease (peripheral vascular disease p=0.012, myocardial infarction, p=0.004, MCA stenosis p<0.001) increased significantly with increasing levels of albuminuria. Albuminuria was also found to be an independent predictor of microvascular and macrovascular disease. CONCLUSIONS/INTERPRETATION: Albuminuria was an independent predictor of increasing levels of vascular risk factors and microvascular and macrovascular disease in this group of Type 2 diabetic patients, and a possible role for albuminuria as a marker of intracranial cerebrovascular disease should be further investigated.postprin

Fungal Communities in Sediments Along a Depth Gradient in the Eastern Tropical Pacific

Deep waters represent the largest biome on Earth and the largest ecosystem of Costa Rica. Fungi play a fundamental role in global biogeochemical cycling in marine sediments, yet, they remain little explored. We studied fungal diversity and community composition in several marine sediments from 16 locations sampled along a bathymetric gradient (from a depth of 380 to 3,474 m) in two transects of about 1,500 km length in the Eastern Tropical Pacific (ETP) of Costa Rica. Sequence analysis of the V7-V8 region of the 18S rRNA gene obtained from sediment cores revealed the presence of 787 fungal amplicon sequence variants (ASVs). On average, we detected a richness of 75 fungal ASVs per sample. Ascomycota represented the most abundant phylum with Saccharomycetes constituting the dominant class. Three ASVs accounted for ca. 63% of all fungal sequences: the yeast Metschnikowia (49.4%), Rhizophydium (6.9%), and Cladosporium (6.7%). We distinguished a cluster composed mainly by yeasts, and a second cluster by filamentous fungi, but we were unable to detect a strong effect of depth and the overlying water temperature, salinity, dissolved oxygen (DO), and pH on the composition of fungal communities. We highlight the need to understand further the ecological role of fungi in deep-sea ecosystems.UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Básicas::Centro de Investigación en Ciencias del Mar y Limnología (CIMAR)UCR::Vicerrectoría de Docencia::Ciencias Básicas::Facultad de Ciencias::Escuela de Biologí

Guidelines for the management of glucocorticoids during the peri-operative period for patients with adrenal insufficiency: Guidelines from the Association of Anaesthetists, the Royal College of Physicians and the Society for Endocrinology UK

These guidelines aim to ensure that patients with adrenal insufficiency are identified and adequately supplemented with glucocorticoids during the peri-operative period. There are two major categories of adrenal insufficiency. Primary adrenal insufficiency is due to diseases of the adrenal gland (failure of the hormone-producing gland), and secondary adrenal insufficiency is due to deficient adrenocorticotropin hormone secretion by the pituitary gland, or deficient corticotropin-releasing hormone secretion by the hypothalamus (failure of the regulatory centres). Patients taking physiological replacement doses of corticosteroids for either primary or secondary adrenal insufficiency are at significant risk of adrenal crisis and must be given stress doses of hydrocortisone during the peri-operative period. Many more patients other than those with adrenal and hypothalamic-pituitary causes of adrenal failure are receiving glucocorticoids as treatment for other medical conditions. Daily doses of prednisolone of 5 mg or greater in adults and 10-15 mg.m-2 hydrocortisone equivalent or greater in children may result in hypothalamo-pituitary-adrenal axis suppression if administered for 1 month or more by oral, inhaled, intranasal, intra-articular or topical routes; this chronic administration of glucocorticoids is the most common cause of secondary adrenal suppression, sometimes referred to as tertiary adrenal insufficiency. A pragmatic approach to adrenal replacement during major stress is required; considering the evidence available, blanket recommendations would not be appropriate, and it is essential for the clinician to remember that adrenal replacement dosing following surgical stress or illness is in addition to usual steroid treatment. Patients with previously undiagnosed adrenal insufficiency sometimes present for the first time following the stress of surgery. Anaesthetists must be familiar with the symptoms and signs of acute adrenal insufficiency so that inadequate supplementation or undiagnosed adrenal insufficiency can be detected and treated promptly. Delays may prove fatal

Adrenal suppression in patients taking inhaled glucocorticoids is highly prevalent and management can be guided by morning cortisol

Context Up to 3% of US and UK populations are prescribed glucocorticoids (GC). Suppression of the hypothalamo–pituitary–adrenal axis with the potential risk of adrenal crisis is a recognized complication of therapy. The 250 μg short Synacthen stimulation test (SST) is the most commonly used dynamic assessment to diagnose adrenal insufficiency. There are challenges to the use of the SST in routine clinical practice, including both the staff and time constraints and a significant recent increase in Synacthen cost. Methods We performed a retrospective analysis to determine the prevalence of adrenal suppression due to prescribed GCs and the utility of a morning serum cortisol for rapid assessment of adrenal reserve in the routine clinical setting. Results In total, 2773 patients underwent 3603 SSTs in a large secondary/tertiary centre between 2008 and 2013 and 17.9% (n=496) failed the SST. Of 404 patients taking oral, topical, intranasal or inhaled GC therapy for non-endocrine conditions, 33.2% (n=134) had a subnormal SST response. In patients taking inhaled GCs without additional GC therapy, 20.5% (34/166) failed an SST and suppression of adrenal function increased in a dose-dependent fashion. Using receiver operating characteristic curve analysis in patients currently taking inhaled GCs, a basal cortisol ≥348 nmol/l provided 100% specificity for passing the SST; a cortisol value <34 nmol/l had 100% sensitivity for SST failure. Using these cut-offs, 50% (n=83) of SSTs performed on patients prescribed inhaled GCs were unnecessary. Conclusion Adrenal suppression due to GC treatment, particularly inhaled GCs, is common. A basal serum cortisol concentration has utility in helping determine which patients should undergo dynamic assessment of adrenal function

Regulation of Lipogenesis by Glucocorticoids and Insulin in Human Adipose Tissue

Patients with glucocorticoid (GC) excess, Cushing's syndrome, develop a classic phenotype characterized by central obesity and insulin resistance. GCs are known to increase the release of fatty acids from adipose, by stimulating lipolysis, however, the impact of GCs on the processes that regulate lipid accumulation has not been explored. Intracellular levels of active GC are dependent upon the activity of 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) and we have hypothesized that 11β-HSD1 activity can regulate lipid homeostasis in human adipose tissue (Chub-S7 cell line and primary cultures of human subcutaneous (sc) and omental (om) adipocytes. Across adipocyte differentiation, lipogenesis increased whilst β-oxidation decreased. GC treatment decreased lipogenesis but did not alter rates of β-oxidation in Chub-S7 cells, whilst insulin increased lipogenesis in all adipocyte cell models. Low dose Dexamethasone pre-treatment (5 nM) of Chub-S7 cells augmented the ability of insulin to stimulate lipogenesis and there was no evidence of adipose tissue insulin resistance in primary sc cells. Both cortisol and cortisone decreased lipogenesis; selective 11β-HSD1 inhibition completely abolished cortisone-mediated repression of lipogenesis. GCs have potent actions upon lipid homeostasis and these effects are dependent upon interactions with insulin. These in vitro data suggest that manipulation of GC availability through selective 11β-HSD1 inhibition modifies lipid homeostasis in human adipocytes

Dehydroepiandrosterone exerts antiglucocorticoid action on human preadipocyte proliferation, differentiation, and glucose uptake

Glucocorticoids increase adipocyte proliferation and differentiation, a process underpinned by the local reactivation of inactive cortisone to active cortisol within adipocytes catalyzed by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). The adrenal sex steroid precursor dehydroepiandrosterone (DHEA) has been shown to inhibit 11β-HSD1 in murine adipocytes; however, rodent adrenals do not produce DHEA physiologically. Here, we aimed to determine the effects and underlying mechanisms of the potential antiglucocorticoid action of DHEA and its sulfate ester DHEAS in human preadipocytes. Utilizing a human subcutaneous preadipocyte cell line, Chub-S7, we examined the metabolism and effects of DHEA in human adipocytes, including adipocyte proliferation, differentiation, 11β-HSD1 expression, and activity and glucose uptake. DHEA, but not DHEAS, significantly inhibited preadipocyte proliferation via cell cycle arrest in the G1 phase independent of sex steroid and glucocorticoid receptor activation. 11β-HSD1 oxoreductase activity in differentiated adipocytes was inhibited by DHEA. DHEA coincubated with cortisone significantly inhibited preadipocyte differentiation, which was assessed by the expression of markers of early (LPL) and terminal (G3PDH) adipocyte differentiation. Coincubation with cortisol, negating the requirement for 11β-HSD1 oxoreductase activity, diminished the inhibitory effect of DHEA. Further consistent with glucocorticoidopposing effects of DHEA, insulin-independent glucose uptake was significantly enhanced by DHEA treatment. DHEA increases basal glucose uptake and inhibits human preadipocyte proliferation and differentiation, thereby exerting an antiglucocorticoid action. DHEA inhibition of the amplification of glucocorticoid action mediated by 11β-HSD1 contributes to the inhibitory effect of DHEA on human preadipocyte differentiation

AKR1C3-mediated adipose androgen generation drives lipotoxicity in women with polycystic ovary syndrome

Context: Polycystic ovary syndrome (PCOS) is a prevalent metabolic disorder, occurring in up to 10% of women of reproductive age. PCOS is associated with insulin resistance and cardiovascular risk. Androgen excess is a defining feature of PCOS and has been suggested as causally associated with insulin resistance; however, mechanistic evidence linking both is lacking. We hypothesized that adipose tissue is an important site linking androgen activation and metabolic dysfunction in PCOS. Methods We performed a human deep metabolic in vivo phenotyping study, examining the systemic and intra-adipose effects of acute and chronic androgen exposure in ten PCOS women, in comparison to ten body mass index-matched healthy controls, complemented by in vitro experiments. Results: PCOS women had increased intra-adipose concentrations of testosterone (p=0.0006) and dihydrotestosterone (p=0.01), with increased expression of the androgen-activating enzyme aldoketoreductase type 1 C3 (AKR1C3, p=0.04) in subcutaneous adipose tissue. Adipose glycerol levels in subcutaneous adipose tissue microdialysate supported in vivo suppression of lipolysis after acute androgen exposure in PCOS (p=0.04). Mirroring this, non-targeted serum metabolomics revealed pro-lipogenic effects of androgens in PCOS women only. In vitro studies showed that insulin increased adipose AKR1C3 expression and activity while androgen exposure increased adipocyte de novo lipid synthesis. Pharmacological AKR1C3 inhibition in vitro decreased de novo lipogenesis. Conclusions: These findings define a novel intra-adipose mechanism of androgen activation that contributes to adipose remodelling and a systemic lipotoxic metabolome, with intra-adipose androgens driving lipid accumulation and insulin resistance in PCOS. AKR1C3 represents a promising novel therapeutic target in PCOS.This work was funded by the Wellcome Trust (Clinical Research Training Fellowship 099909, to MOR, and Project Grant 092283, to WA), the BBSRC (BB/L006340/1, to DH) and the National Institute of Health Research (NIHR) UK