Estrogens protect male mice from obesity complications and influence glucocorticoid metabolism.

BACKGROUND: Although the prevalence of obesity is higher among women than men, they are somewhat protected from the associated cardiometabolic consequences. The increase in cardiovascular disease risk seen after the menopause suggests a role for estrogens. There is also growing evidence for the importance of estrogen on body fat and metabolism in males. We hypothesized that that estrogen administration would ameliorate the adverse effects of obesity on metabolic parameters in males. METHODS: Male and female C57Bl/6 mice were fed control or obesogenic (DIO) diets from 5 weeks of age until adulthood. Glucose tolerance testing was performed at 13 weeks of age. Mice were killed at 15 weeks of age and liver and adipose tissue were collected for analysis of gene expression. A second cohort of male mice underwent the same experimental design with the addition of estradiol pellet implantation or sham surgery at 6 weeks. RESULTS: DIO males had greater mesenteric adipose deposition and more severe increases in plasma glucose, insulin and lipids than females. Treatment of males with estradiol from 6 weeks of age prevented DIO-induced increases in adipose tissue mass and alterations in glucose-insulin homeostasis. We also identified sex differences in the transcript levels and activity of hepatic and adipose glucocorticoid metabolizing enzymes. Estrogen treatment feminized the pattern of DIO-induced changes in glucocorticoid metabolism, rendering males similar to females. CONCLUSIONS: Thus, DIO induces sex-specific changes in glucose-insulin homeostasis, which are ameliorated in males treated with estrogen, highlighting the importance of sex steroids in metabolism. Given that altered peripheral glucocorticoid metabolism has been observed in rodent and human obesity, our results also suggest that sexually dimorphic expression and activity of glucocorticoid metabolizing enzymes may have a role in the differential metabolic responses to obesity in males and females.

Diet-induced weight loss has chronic tissue-specific effects on glucocorticoid metabolism in overweight postmenopausal women.

BACKGROUND/OBJECTIVES: Tissue-specific glucocorticoid metabolism is altered in obesity, and may increase cardiovascular risk. This dysregulation is normalized by short-term calorie restriction and weight loss, an effect that varies with dietary macronutrient composition. However, tissue-specific glucocorticoid metabolism has not been studied during long-term (>6 months) dietary interventions. Therefore our aim was to test whether long-term dietary interventions, either a paleolithic-type diet (PD) or a diet according to Nordic nutrition recommendations (NNR) could normalize tissue-specific glucocorticoid metabolism in overweight and obese women. SUBJECTS/METHODS: Forty-nine overweight/obese postmenopausal women were randomized to a paleolithic diet or a diet according to NNR for 24 months. At baseline, 6 and 24 months anthropometric measurements, insulin sensitivity, excretion of urinary glucocorticoid metabolites in 24-hour collections, conversion of orally administered cortisone to plasma cortisol and transcript levels of 11ß hydroxysteroid dehydrogenase type 1 (11ßHSD1) in subcutaneous adipose tissue were studied. RESULTS: Both diet groups achieved significant and sustained weight loss. Weight loss with the PD was greater than on NNR diet after 6 months (P<0.001) but similar at 24 months. Urinary measurement of 5α-reductase activity was increased after 24 months in both groups compared with baseline (P<0.001). Subcutaneous adipose tissue 11ßHSD1 gene expression decreased at 6 and 24 months in both diet groups (P=0.036). Consistent with increased liver 11ßHSD1, conversion of oral cortisone to cortisol increased at 6 months (P=0.023) but was unchanged compared with baseline by 24 months. CONCLUSIONS: Long-term weight loss in postmenopausal women has tissue-specific and time-dependent effects on glucocorticoid metabolism. This may alter local-tissue cortisol exposure contributing to improved metabolic function during weight loss.

Glucocorticoid receptor gene expression in adipose tissue and associated metabolic risk in black and white South African women.

BACKGROUND: Black women have lower visceral adipose tissue (VAT) but are less insulin sensitive than white women; the mechanisms responsible are unknown. OBJECTIVE: The study aimed to test the hypothesis that variation in subcutaneous adipose tissue (SAT) sensitivity to glucocorticoids might underlie these differences. METHODS: Body fatness (dual energy X-ray absorptiometry) and distribution (computerized tomography), insulin sensitivity (SI, intravenous and oral glucose tolerance tests), and expression of 11ß-hydroxysteroid dehydrogenase-1 (11HSD1), hexose-6-phosphate dehydrogenase and glucocorticoid receptor-α (GRα), as well as genes involved in adipogenesis and inflammation were measured in abdominal deep SAT, superficial SAT and gluteal SAT (GLUT) depots of 56 normal-weight or obese black and white premenopausal South African (SA) women. We used a combination of univariate and multivariate statistics to evaluate ethnic-specific patterns in adipose gene expression and related body composition and insulin sensitivity measures. RESULTS: Although 11HSD1 activity and mRNA did not differ by ethnicity, GRα mRNA levels were significantly lower in SAT of black compared with white women, particularly in the GLUT depot (0.52±0.21 vs 0.91±0.26 AU, respectively, P<0.01). In black women, lower SAT GRα mRNA levels were associated with increased inflammatory gene transcript levels and abdominal SAT area, and reduced adipogenic gene transcript levels, VAT/SAT ratio and SI. Abdominal SAT 11HSD1 activity associated with increased VAT area and decreased SI in white, but not in black women. CONCLUSIONS: In black SA women, downregulation of GRα mRNA levels with obesity and reduced insulin sensitivity, possibly via increased SAT inflammation, is associated with reduced VAT accumulation.

Effects of acute glucocorticoid blockade on metabolic dysfunction in patients with Type 2 diabetes with and without fatty liver.

To investigate the potential of therapies which reduce glucocorticoid action in patients with Type 2 diabetes we performed a randomized, double-blinded, placebo-controlled crossover study of acute glucocorticoid blockade, using the glucocorticoid receptor antagonist RU38486 (mifepristone) and cortisol biosynthesis inhibitor (metyrapone), in 14 men with Type 2 diabetes. Stable isotope dilution methodologies were used to measure the rates of appearance of glucose, glycerol, and free fatty acids (FFAs), including during a low-dose (10 mU·m⁻² ·min⁻¹) hyperinsulinemic clamp, and subgroup analysis was conducted in patients with high or low liver fat content measured by magnetic resonance spectroscopy (n = 7/group). Glucocorticoid blockade lowered fasting glucose and insulin levels and improved insulin sensitivity of FFA and glycerol turnover and hepatic glucose production. Among this population with Type 2 diabetes high liver fat was associated with hyperinsulinemia, higher fasting glucose levels, peripheral and hepatic insulin resistance, and impaired suppression of FFA oxidation and FFA and glycerol turnover during hyperinsulinemia. Glucocorticoid blockade had similar effects in those with and without high liver fat. Longer term treatments targeting glucocorticoid action may be useful in Type 2 diabetes with and without fatty liver.

A history of previous gestational diabetes mellitus is associated with adverse changes in insulin secretion and VLDL metabolism independently of increased intrahepatocellular lipid.

AIMS/HYPOTHESIS: We have previously reported a high prevalence of non-alcoholic fatty liver disease (NAFLD) among women with previous gestational diabetes mellitus (pGDM). We wanted to confirm that intrahepatocellular lipid (IHCL) is associated with pGDM independently of adiposity and determine: (1) if VLDL metabolism is dysregulated; and (2) the extent to which NAFLD and IHCL account for the dysmetabolic phenotype in pGDM. METHODS: We analysed data from a cohort of 234 women (114 with pGDM) and identified effects of pGDM on lipid and glucoregulation that were independent of ultrasound-diagnosed NAFLD. We then measured IHCL by MR spectroscopy in a representative subgroup (n = 36) and conducted detailed metabolic studies (IVGTT, VLDL apolipoprotein B [apoB] kinetics and palmitate turnover) and measurement of regional body fat by MRI to demonstrate effects of IHCL that were independent of a history of pGDM. RESULTS: pGDM was associated with increased IHCL (p = 0.04) after adjustment for adiposity. Independently of IHCL, pGDM was associated with a lower IVGTT disposition index (p = 0.02) and acute insulin response to glucose (pGDM+/NAFLD-, 50% lower; pGDM+/NAFLD+, 36% lower; effect of pGDM, p = 0.03), increased VLDL apoB pool size (pGDM+/NAFLD-, 3.1-fold higher; pGDM+/NAFLD+, 1.2-fold higher; effect of pGDM, p = 0.02) and, at borderline significance (p = 0.05), increased rate of VLDL apoB synthesis. CONCLUSIONS/INTERPRETATION: pGDM is associated with increased IHCL independently of adiposity. The increased liver fat contributes to the phenotype, but pGDM status is independently associated with diminished insulin secretion and (shown for the first time) augmented VLDL metabolism. IHCL with pGDM may compound a dysmetabolic phenotype.

Glucocorticoid treatment regimen and health outcomes in adults with congenital adrenal hyperplasia.

BACKGROUND: Adults with congenital adrenal hyperplasia (CAH) are treated with a wide variety of glucocorticoid treatment regimens. OBJECTIVE, DESIGN AND METHODS: To test whether drug dose and timing of glucocorticoid treatment regimen impacts on health outcomes. This was a cross-sectional study of 196 adult CAH patients in whom treatment and health outcomes were measured. Glucocorticoid dose was converted to prednisolone dose equivalent (PreDEq) using three published formulae. Associations between the type of glucocorticoid regimen and PreDEq with specific health outcome variables were tested using partial correlation and principal components analysis (PCA). RESULTS: Patients on dexamethasone had lower androgens and ACTH but greater insulin resistance compared with those receiving hydrocortisone or prednisolone. Dexamethasone dose and once daily administration were associated with insulin resistance. Partial correlation analysis adjusted for age and sex showed PreDEq weakly correlated (r < 0·2) with blood pressure and androstenedione. Mutation severity was associated with increased PreDEq (F(3,141)  = 4·4, P < 0·01). In PCA, 3 PCs were identified that explained 62% of the total variance (r(2) ) in observed variables. Regression analysis (age and sex adjusted) confirmed that PC2, reflecting disease control (androstenedione, 17-hydroxypregesterone and testosterone), and PC3, reflecting blood pressure and mutations (systolic and diastolic blood pressure and mutation severity), related directly to PreDEq (r(2)  = 23%, P < 0·001). CONCLUSIONS: In adults with congenital adrenal hyperplasia, dexamethasone use was associated with lower androgens but greater insulin resistance, and increasing glucocorticoid dose associated with increased blood pressure, poor disease control and mutation severity.

Contribution of local regeneration of glucocorticoids to tissue steroid pools.

11ß-Hydroxysteroid dehydrogenase 1 (11ßHSD1) is a drug target to attenuate adverse effects of chronic glucocorticoid excess. It catalyses intracellular regeneration of active glucocorticoids in tissues including brain, liver and adipose tissue (coupled to hexose-6-phosphate dehydrogenase, H6PDH). 11ßHSD1 activity in individual tissues is thought to contribute significantly to glucocorticoid levels at those sites, but its local contribution vs glucocorticoid delivery via the circulation is unknown. Here, we hypothesised that hepatic 11ßHSD1 would contribute significantly to the circulating pool. This was studied in mice with Cre-mediated disruption of Hsd11b1 in liver (Alac-Cre) vs adipose tissue (aP2-Cre) or whole-body disruption of H6pdh. Regeneration of [9,12,12-2H3]-cortisol (d3F) from [9,12,12-2H3]-cortisone (d3E), measuring 11ßHSD1 reductase activity was assessed at steady state following infusion of [9,11,12,12-2H4]-cortisol (d4F) in male mice. Concentrations of steroids in plasma and amounts in liver, adipose tissue and brain were measured using mass spectrometry interfaced with matrix-assisted laser desorption ionisation or liquid chromatography. Amounts of d3F were higher in liver, compared with brain and adipose tissue. Rates of appearance of d3F were ~6-fold slower in H6pdh-/- mice, showing the importance for whole-body 11ßHSD1 reductase activity. Disruption of liver 11ßHSD1 reduced the amounts of d3F in liver (by ~36%), without changes elsewhere. In contrast disruption of 11ßHSD1 in adipose tissue reduced rates of appearance of circulating d3F (by ~67%) and also reduced regenerated of d3F in liver and brain (both by ~30%). Thus, the contribution of hepatic 11ßHSD1 to circulating glucocorticoid levels and amounts in other tissues is less than that of adipose tissue.

Increased prevalence of non-alcoholic fatty liver disease in European women with a history of gestational diabetes.

AIMS/HYPOTHESIS: Non-alcoholic fatty liver disease (NAFLD) is common in type 2 diabetes but it is unknown whether NAFLD is prevalent in European women at risk of type 2 diabetes. We studied the prevalence of, and risk factors for, NAFLD in European women with previous gestational diabetes (GDM) at high risk of type 2 diabetes. METHODS: A total of 110 women with previous GDM and 113 without previous GDM, with non-diabetic glucose tolerance were recruited retrospectively from antenatal databases. Participants underwent liver ultrasound scan examination, anthropometry and blood sampling for liver function tests and to determine levels of fasting lipids, NEFA and insulin and glucose concentrations in order to derive insulin sensitivity and insulin secretion indices (HOMA%S and HOMA%B, respectively). RESULTS: There was no significant difference in BMI in women with previous GDM compared with those without previous GDM (28.9 ± 0.6 vs. 27.9 ± 0.6 kg/m(2), respectively; p = 0.12). Women with previous GDM had higher fasting and 2 h glucose concentrations following a 75 g OGTT ([mean ± SEM] fasting glucose 5.3 ± 0.1 vs. 5.1 ± 0.1 mmol/l, p = 0.02; 2 h glucose 6.8 ± 0.2 vs. 5.8 ± 0.3 mmol/l, p = 0.02), dyslipidaemia (LDL-cholesterol 3.3 ± 0.1 vs. 2.8 ± 0.1 mmol/l; HDL-cholesterol [median {interquartile range}] 1.3 [1.2-1.6] vs. 1.8 [1.5-1.9] mmol/l; triacylglycerol 1.3 [0.9-1.6] vs. 1.0 [0.7-1.7] mmol/l, all p ≤ 0.03), higher insulin secretion and lower insulin sensitivity. NAFLD prevalence was greater in women with previous GDM compared with those without previous GDM: 38% (95% CI 28-47%) vs. 17% (95% CI 10-24%), p = 0.001. In multiple logistic regression analysis, lower insulin sensitivity and raised serum alanine transaminase concentrations were associated with NAFLD. CONCLUSIONS/INTERPRETATION: NAFLD is prevalent in European women with previous GDM. Impaired insulin sensitivity and increased liver transaminase activity are closely associated with NAFLD in these women.

High fat feeding impairs endothelin-1 mediated vasoconstriction through increased iNOS-derived nitric oxide.

Rats fed a high fat diet develop increased adiposity and oxidative stress leading to impaired vasodilation. The purpose of the present study was to examine the effects of high fat-induced increases in adiposity and oxidative stress on vasoconstrictor reactivity of isolated mesenteric arteries. We hypothesized that rats with more adiposity would develop oxidative stress-potentiated increases in iNOS-derived nitric oxide leading to diminished vasoconstriction. Male Sprague-Dawley rats were fed either a control (Chow) or high fat diet for 6 weeks. The roles of oxidative stress and iNOS in the impaired vasoconstrictor responses to endothelin-1 were characterized in small mesenteric arteries. Rats fed the HFD developed significantly more adiposity compared to Chow rats. Plasma levels of nitric oxide and the inflammatory factor tumor necrosis factor α were significantly higher in high fat fed rats compared to Chow rats (nitric oxide: 95.36±19.3 vs. 38.96±6.7 µM; tumor necrosis factor α: 598±111.4 vs. 292±71.8 pg/ml, respectively). Despite exhibiting elevated systolic blood pressure compared to Chow rats (153.5±2.4 vs. 137.5±2.7 mm Hg), endothelin-1 mediated vasoconstriction was impaired in isolated mesenteric arteries from high fat fed rats but was normalized by individual or combined inhibition of nitric oxide synthase, iNOS, or oxidative stress. Therefore, oxidative stress and iNOS are involved in the attenuation of endothelin-1 mediated vasoconstriction observed in isolated mesenteric arteries from high fat fed rats.

Symptoms of depression but not anxiety are associated with central obesity and cardiovascular disease in people with type 2 diabetes: the Edinburgh Type 2 Diabetes Study.

AIMS/HYPOTHESIS: The aim of the study was to identify risk factors for depression and anxiety in a well-characterised cohort of individuals with type 2 diabetes mellitus. METHODS: We used baseline data from participants (n = 1,066, 48.7% women, aged 67.9 +/- 4.2 years) from the Edinburgh Type 2 Diabetes Study. Symptoms of anxiety and depression were assessed using the Hospital Anxiety and Depression Scale (HADS). Obesity was characterised according to both overall (body mass index, fat mass) and abdominal (waist circumference) measurements. Cardiovascular disease was assessed by questionnaire, physical examination and review of medical records. Stepwise multiple linear regression was performed to identify explanatory variables related to either anxiety or depression HADS scores. RESULTS: Abdominal obesity (waist circumference) and cardiovascular disease (ischaemic heart disease and ankle-brachial pressure index) were related to depression but not anxiety. Lifetime history of severe hypoglycaemia was associated with anxiety. Other cardiovascular risk factors or microvascular complications were not related to either anxiety or depressive symptoms. CONCLUSIONS/INTERPRETATION: Depression but not anxiety is associated with abdominal obesity and cardiovascular disease in people with type 2 diabetes mellitus. This knowledge may help to identify depressive symptoms among patients with type 2 diabetes who are at greatest risk.

Increased clearance of cortisol by 5beta-reductase in a subgroup of women with adrenal hyperandrogenism in polycystic ovary syndrome.

OBJECTIVE: Increased peripheral metabolism of cortisol may explain compensatory ACTH-dependent adrenal steroidogenesis and hence hyperandrogenism in polycystic ovary syndrome (PCOS). Previous studies have described an increased 5alpha-reduction of cortisol or impaired regeneration of cortisol by 11beta-HSD1 in PCOS. However, these observations may be confounded by obesity. Moreover, the relationship between alterations in cortisol metabolism and the extent of adrenal androgen hyper-secretion in response to ACTH has not been established. This study aimed to examine the association between cortisol metabolism and ACTH-dependent adrenal hyperandrogenism in PCOS, independently of obesity. DESIGN: We compared 90 PCOS women (age 18-45 yr) stratified by adrenal androgen responses to ACTH1-24 and 45 controls matched for age and body weight. METHODS: PCOS women were stratified as normal responders (NR), intermediate responders (IR), and high responders (HR) to 250 microg ACTH1-24: NR (no.=27) had androstenedione and DHEA responses within 2 SD of the mean in controls; IR (no.=43) had DHEA responses >2 SD above controls; HR (no.=20) had both androstenedione and DHEA responses >2 SD above controls. RESULTS: All groups were similar for age, body weight, and body fat distribution. Basal testosterone, androstenedione, and 5alpha-dihydrotestosterone plasma levels were similarly elevated among the 3 groups of PCOS compared with controls, whereas basal DHEA-S was higher in HR (2.8+/-1.2 microg/ml) and IR (2.4+/-1.1 microg/ml) than in NR (1.8+/-0.8 microg/ml) and controls (1.7+/-0.6 microg/ml). The HR group had the lowest basal plasma cortisol levels (101+/-36 ng/ml vs IR 135+/-42 ng/ml, NR 144+/-48 ng/ml, and controls 165+/-48 ng/ml; all p<0.01), but the greatest cortisol response to ACTH1-24 (Delta(60-0)cortisol 173+/-60 ng/ml vs IR 136+/-51 ng/ml, NR 114+/-50 ng/ml, and controls 127+/-50 ng/ml; all p<0.01), and the highest urinary excretion of total and 5beta-reduced cortisol metabolites (eg 5beta-tetrahydrocortisol/ cortisol ratio 25.2+/-15.3 vs IR 18.8+/-10.7, NR 19.7+/-11.4, and controls 17.2+/-13.7; all p<0.05). There were no differences in urinary excretion of 5alpha-reduced cortisol metabolites or in 5alpha-dihydrotestosterone/testosterone ratio between groups. CONCLUSIONS: Adrenal androgen excess in PCOS is associated with increased inactivation of cortisol by 5beta-reductase that may lower cortisol blood levels and stimulate ACTH-dependent steroidogenesis.

Idiopathic intracranial hypertension: can studies of obesity provide the key to understanding pathogenesis?

The pathogenesis of idiopathic intracranial hypertension (IIH) is poorly understood. Several mechanisms have been suggested, but no one mechanism has been able to account for all manifestations of the disease. Although IIH predominantly affects obese, premenopausal women, little is known about whether or how the obesity contributes to the IIH. Obesity is a heterogeneous condition, consisting of different phenotypes that are influenced by the regional distribution of adipose tissue. This review explores the literature to integrate current knowledge on the relationships between obesity and IIH. The review evaluates the hypotheses that dysregulation of insulin, glucose metabolism, sex hormones, adipokines, glucocorticoids, lipids and free fatty acids in obesity could predispose to IIH. One potential common pathway linking metabolic disorders to the pathogenesis of IHH is a thrombotic tendency due to dysregulation of haemostatic risk factors. This could cause either occult cerebral sinus thrombosis or partial thrombosis of the parasagittal venous lacunae, with subsequent impaired resorption of cerebrospinal fluid and venous hypertension. Investigations that evaluate obesity, fat metabolism, endocrinological dysregulation and thrombotic tendency in patients with IIH are required so that pathogenic mechanisms can be clarified and management strategies in IIH can be improved.

Quantification of 11ß-hydroxysteroid dehydrogenase 1 kinetics and pharmacodynamic effects of inhibitors in brain using mass spectrometry imaging and stable-isotope tracers in mice.

11ß-Hydroxysteroid dehydrogenase 1 (11ß-HSD1; EC 1.1.1.146) generates active glucocorticoid hormones. Small molecule inhibitors have been developed to target 11ß-HSD1 for the treatment of dementia; these must enter brain subregions, such as the hippocampus, to be effective. We previously reported mass spectrometry imaging measurement of murine tissue steroids, and deuterated steroid tracer infusion quantification of 11ß-HSD1 turnover in humans. Here, these tools are combined to assess tissue pharmacokinetics and pharmacodynamics of an 11ß-HSD1 inhibitor that accesses the brain. [9,11,12,12-2H]4-Cortisol was infused (1.75 mg/day) by minipump for 2 days into C57Bl6 mice (male, age 12 weeks, n = 3/group) after which an 11ß-HSD1 inhibitor (UE2316) was administered (25 mg/kg oral gavage) and animals culled immediately or 1, 2 and 4 h post-dosing. Mice with global genetic disruption of Hsd11B1 were studied similarly. Turnover of d4-cortisol to d3-cortisone (by loss of the 11-deuterium) and regeneration of d3-cortisol (by 11ß-HSD1-mediated reduction) were assessed in plasma, liver and brain using matrix assisted laser desorption ionization coupled to Fourier transform cyclotron resonance mass spectrometry. The tracer d4-cortisol was detected in liver and brain following a two day infusion. Turnover to d3-cortisone and on to d3-cortisol was slower in brain than liver. In contrast, d3-cortisol was not detected in mice lacking 11ß-HSD1. UE2316 impaired d3-cortisol generation measured in whole body (assessed in plasma; 53.1% suppression in rate of appearance in d3-cortisol), liver and brain. Differential inhibition in brain regions was observed; active glucocorticoids were suppressed to a greater in extent hippocampus or cortex than in amygdala. These data confirm that the contribution of 11ß-HSD1 to the tissue glucocorticoid pool, and the consequences of enzyme inhibition on active glucocorticoid concentrations, are substantial, including in the brain. They further demonstrate the value of mass spectrometry imaging in pharmacokinetic and pharmacodynamic studies.

Effects of increased sodium delivery on distal tubular sodium reabsorption with and without volume expansion in man.

The separate effects of volume expansion and of increased delivery of sodium on sodium reabsorption in the diluting segment of the distal nephron were studied in man. In six normal subjects during a sustained water diuresis, sodium delivery to the distal nephron was increased without volume expansion by the administration of acetazolamide. In these subjects, free water clearance rose linearly as a function of urine flow. In five patients with complete, central diabetes insipidus, distal sodium delivery was increased by the infusion of hypertonic saline during a sustained water diuresis. In four of these five patients, changes in free water clearance were also observed during hypertonic saline diuresis in the presence of distal blockade of sodium reabsorption with chlorothiazide. At high rates of distal delivery the following observations were made: (a) free water clearance was lower and fractional sodium excretion higher during saline diuresis compared to acetazolamide diuresis; (b) although free water clearance was moderately reduced by chlorothiazide at low rates of urine flow, there was no difference in free water clearance between saline loading alone and saline plus chlorothiazide at high rates of urine flow; and (c) during saline loading free water clearance rose without evidence of a limit when increased distal delivery was accompanied by spontaneous increases in glomerular filtration rate, but tended toward a limit when glomerular filtration rate remained constant. The data indicate that during acute volume expansion with saline, there is a decrease in the fraction of delivered sodium reabsorbed in the distal nephron when compared to the response of the distal nephron to comparable increases in distal sodium delivery in the absence of volume expansion.

Impaired microvascular dilatation and capillary rarefaction in young adults with a predisposition to high blood pressure.

Increased vascular resistance in essential hypertension occurs mainly in microvessels with luminal diameters < 100 microm. It is not known whether abnormalities in these vessels are a cause or consequence of high blood pressure (BP). We studied 105 men (aged 23-33 yr) in whom predisposition to high blood pressure has been characterized by both their own BP and those of their parents. Factors that are secondary to high BP correlate with offspring BP irrespective of parental BP, but factors that are components of the familial predisposition to high BP are more closely associated with higher BP in offspring whose parents also have high BP. Offspring with high BP whose parents also have high BP had impaired dermal vasodilatation in the forearm following ischemia and heating (289+/-27 [n = 25] versus 529+/-40 [n = 26], 476+/-38 [n = 30], and 539+/-41 flux units [n = 24] in other groups; P < 0.0001) and fewer capillaries on the dorsum of the finger (23+/-0.8 capillaries/0.25 mm2 versus 26+/-0.8 in all other groups; P < 0.003). Except for BP, other hemodynamic indices (including cardiac output and forearm vascular resistance) were not different. The dermal vessels of men who express a familial predisposition to high BP exhibit increased minimum resistance and capillary rarefaction. Defective angiogenesis may be an etiological component in the inheritance of high BP.

Glucocorticoids and 11beta-hydroxysteroid dehydrogenase type 1 in obesity and the metabolic syndrome.

Central obesity is associated with type 2 diabetes mellitus, hypertension and dyslipidaemia. This cluster of risk factors is known as the metabolic syndrome, and also occurs in people with primary glucocorticoid excess (Cushing's syndrome). Exogenous glucocorticoid use also increases the risk of cardiovascular disease. Circulating glucocorticoid concentrations are tightly controlled by the hypothalamic-pituitary-adrenal axis, however tissue glucocorticoid levels are also enhanced by the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). Transgenic overexpression of 11beta-HSD1 in either adipose tissue or the liver in mice causes components of the metabolic syndrome, while transgenic deletion of 11beta-HSD1 prevents adverse metabolic complications of obesity. Although plasma glucocorticoid levels are not elevated in obesity, dysregulation of 11beta-HSD1 is observed with decreased activity in the liver and increased activity in adipose tissue. 11beta-HSD1 is highly regulated, and dietary composition may be a powerful determinant of activity. Polymorphisms in the 11beta-HSD1 gene are also associated with components of the metabolic syndrome. Inhibition of this enzyme appears to be an attractive option to treat metabolic disease. Selective 11beta-HSD1 inhibitors in rodents cause weight loss, improve insulin sensitivity and delay progression of cardiovascular disease. Trials in humans though will be the ultimate test to determine if inhibition of 11beta-HSD1 offers a new tool in the treatment of metabolic disease.

Age-related decrease of the chorda tympani nerve terminal field in the nucleus of the solitary tract is prevented by dietary sodium restriction during development.

Institution of a low-NaCl diet beginning at embryonic day 3 and continued throughout pre- and postnatal development has widespread effects on the neuroanatomical organization of the first gustatory relay in the nucleus of the solitary tract. To determine when these effects are expressed postnatally, the terminal field of the chorda tympani nerve was compared between sodium-restricted and sodium-replete rats at postnatal days 15-17, postnatal days 25-27, postnatal days 35-37, and adults. Total terminal fields were significantly larger in postnatal days 35-37 and adult sodium-restricted rats compared with aged-matched controls. The group-related differences appear related more to a remodeling of the terminal field in the dorsal zone of the terminal field in controls. Specifically, the terminal field volume in the dorsal zone in controls decreased dramatically from postnatal days 25-27 to postnatal days 35-37 and then again from postnatal days 35-37 to adulthood. In contrast, the fields did not change during development in sodium-restricted rats. These findings suggest that remodeling of the chorda tympani field occurs in controls at about the developmental period of taste response maturation. The lack of remodeling in sodium-restricted rats may be explained by a corresponding lack of functional response development to sodium salts. These results also illustrate the specificity and extent of how early dietary manipulations shape the developing brainstem.

Altered vascular contractility in adult female rats with hypertension programmed by prenatal glucocorticoid exposure.

Excessive exposure to glucocorticoids during gestation reduces birth weight and induces permanent hypertension in adulthood. The mechanisms underlying this programmed elevation of blood pressure have not been established. We hypothesised that prenatal glucocorticoid exposure may lead to vascular dysfunction in adulthood. Pregnant rats received dexamethasone (Dex) (100 microg/kg, s.c.) or vehicle (control) daily throughout pregnancy. Blood pressure was elevated (students t-test, unpaired; P < 0.05) in adult female offspring (aged 12-16 weeks) of Dex-treated mothers (148.0 +/- 3.6 mmHg, n=10) compared with the control group (138.0 +/- 2.5 mmHg, n=8). Vascular responsiveness in aortae and mesenteric arteries was differentially affected by prenatal Dex: aortae were less responsive to angiotensin II, whereas mesenteric arteries were more responsive to norepinephrine, vasopressin and potassium (mesenteric arteries respond poorly to angiotensin II in vitro). Acetylcholine-mediated, endothelium-dependent relaxation was similar in both groups. Prenatal exposure to Dex had no effect on blood pressure or aldosterone response to acute (15 min, i.v.) infusion of angiotensin II (75 ng/kg per min). In contrast, chronic (2-week, s.c.) infusion of angiotensin II (100 ng/kg per min) produced a greater elevation (P < 0.05) of blood pressure in Dex-treated rats (150.0 +/- 3.6 mmHg) than in controls (135.3 +/- 5.4 mmHg), and aldosterone levels were higher in Dex-treated animals. There was no angiotensin II-induced medial hypertrophy/hyperplasia in mesenteric arteries from Dex-treated rats. These results indicate that vascular function is altered in a region-specific manner in rats with glucocorticoid-programmed hypertension. Despite a striking increase in mesenteric artery contraction in Dex-treated rats, in vivo studies suggest that abnormalities of the renin-angiotensin-aldosterone system, rather than enhanced vascular contractility, may be responsible for the elevation of blood pressure in these animals.

Endothelial cell dysfunction in mice after transgenic knockout of type 2, but not type 1, 11beta-hydroxysteroid dehydrogenase.

BACKGROUND: 11beta-Hydroxysteroid dehydrogenase (11betaHSD) isozymes catalyze the interconversion of active and inactive glucocorticoids, allowing local regulation of corticosteroid receptor activation. Both are present in the vessel wall; here, using mice with selective inactivation of 11betaHSD isozymes, we test the hypothesis that 11betaHSDs influence vascular function. METHODS AND RESULTS: Thoracic aortas were obtained from weight-matched male wild-type (MF1x129 cross(+/+)), 11betaHSD1(-/-), and 11betaHSD2(-/-) mice. mRNA for both isozymes was detected in wild-type aortas by RT-PCR. 11betaHSD activity in aortic homogenates (48.81+/-4.65% conversion) was reduced in both 11betaHSD1(-/-) (6.36+/-2.47% conversion; P<0.0002) and 11betaHSD2(-/-) (24.71+/-3.69; P=0.002) mice. Functional responses were unaffected in aortic rings isolated from 11betaHSD1(-/-) mice. In contrast, aortas from 11betaHSD2(-/-) mice demonstrated selectively enhanced constriction to norepinephrine (E(max) 4.28+/-0.56 versus 1.72+/-0.47 mN/mm; P=0.004) attributable to impaired endothelium-derived nitric oxide activity. Relaxation responses to endothelium-dependent and -independent vasodilators were also impaired. To control for chronic renal mineralocorticoid excess, MF1 mice were treated with fludrocortisone (16 weeks) but did not reproduce the functional changes observed in 11betaHSD2(-/-) mice. CONCLUSIONS: Although both 11betaHSD isozymes are present in the vascular wall, reactivation of glucocorticoids by 11betaHSD1 does not influence aortic function. Mice with 11betaHSD2 knockout, however, have endothelial dysfunction causing enhanced norepinephrine-mediated contraction. This appears to be independent of renal sodium retention and may contribute to hypertension in 11betaHSD2 deficiency.

Adrenocortical, autonomic, and inflammatory causes of the metabolic syndrome: nested case-control study.

BACKGROUND: The causes of metabolic syndrome (MS), which may be a precursor of coronary disease, are uncertain. We hypothesize that disturbances in neuroendocrine and cardiac autonomic activity (CAA) contribute to development of MS. We examine reversibility and the power of psychosocial and behavioral factors to explain the neuroendocrine adaptations that accompany MS. METHODS AND RESULTS: This was a double-blind case-control study of working men aged 45 to 63 years drawn from the Whitehall II cohort. MS cases (n=30) were compared with healthy controls (n=153). Cortisol secretion, sensitivity, and 24-hour cortisol metabolite and catecholamine output were measured over 2 days. CAA was obtained from power spectral analysis of heart rate variability (HRV) recordings. Twenty-four-hour cortisol metabolite and normetanephrine (3-methoxynorepinephrine) outputs were higher among cases than controls (+ 0.49, +0.45 SD, respectively). HRV and total power were lower among cases (both -0.72 SD). Serum interleukin-6, plasma C-reactive protein, and viscosity were higher among cases (+0.89, +0.51, and +0.72 SD). Lower HRV was associated with higher normetanephrine output (r=-0.19; P=0.03). Among former cases (MS 5 years previously, n=23), cortisol output, heart rate, and interleukin-6 were at the level of controls. Psychosocial factors accounted for 37% of the link between MS and normetanephrine output, and 7% to 19% for CAA. Health-related behaviors accounted for 5% to 18% of neuroendocrine differences. CONCLUSIONS: Neuroendocrine stress axes are activated in MS. There is relative cardiac sympathetic predominance. The neuroendocrine changes may be reversible. This case-control study provides the first evidence that chronic stress may be a cause of MS. Confirmatory prospective studies are required.