RESUMEN
5α-Tetrahydrocorticosterone (5αTHB) is an effective topical anti-inflammatory agent in mouse, with less propensity to cause skin thinning and impede new blood vessel growth compared with corticosterone. Its anti-inflammatory effects were not prevented by RU38486, a glucocorticoid receptor antagonist, suggesting alternative mechanisms. The hypothesis that 5αTHB directly inhibits angiogenesis to a lesser extent than hydrocortisone was tested, focussing on glucocorticoid receptor mediated actions. New vessel growth from aortae from C57BL/6 male mice was monitored in culture, in the presence of 5αTHB, hydrocortisone (mixed glucocorticoid/mineralocorticoid receptor agonist) or the selective glucocorticoid receptor agonist dexamethasone. Transcript profiles were studied, as was the role of the glucocorticoid receptor, using the antagonist, RU38486. Ex vivo, 5αTHB suppressed vessel growth from aortic rings, but was less potent than hydrocortisone (EC50 2512 nM 5αTHB, versus 762 nM hydrocortisone). In contrast to conventional glucocorticoids, 5αTHB did not alter expression of genes related to extracellular matrix integrity or inflammatory signalling, but caused a small increase in Per1 transcript, and decreased transcript abundance of Pecam1 gene. RU38486 did not antagonise the residual effects of 5αTHB to suppress vessel growth or regulate gene expression, but modified effects of dexamethasone. 5αTHB did not alter expression of glucocorticoid-regulated genes Fkbp51 and Hsd11b1, unlike hydrocortisone and dexamethasone. In conclusion, compared with hydrocortisone, 5αTHB exhibits limited suppression of angiogenesis, at least directly in blood vessels and probably independent of the glucocorticoid receptor. Discriminating the mechanisms employed by 5αTHB may provide the basis for the development of novel safer anti-inflammatory drugs for topical use.
Asunto(s)
Corticosterona , Glucocorticoides , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Corticosterona/análogos & derivados , Corticosterona/farmacología , Dexametasona/farmacología , Glucocorticoides/farmacología , Hidrocortisona/farmacología , Masculino , Ratones , Ratones Endogámicos C57BL , Mifepristona/farmacología , Neovascularización Patológica , Receptores de Glucocorticoides/metabolismoRESUMEN
[This corrects the article DOI: 10.1371/journal.pone.0174847.].
RESUMEN
Mild traumatic brain injury (mTBI), or concussion, is the most common type of traumatic brain injury. With mTBI comes symptoms that include headaches, fatigue, depression, anxiety and irritability, as well as impaired cognitive function. Symptom resolution is thought to occur within 3 months post-injury, with the exception of a small percentage of individuals who are said to experience persistent post-concussion syndrome. The number of individuals who experience persistent symptoms appears to be low despite clear evidence of longer-term pathophysiological changes resulting from mTBI. In light of the incongruency between these longer-term changes in brain pathology and the number of individuals with longer-term mTBI-related symptoms, particularly impaired cognitive function, we performed a scoping review of the literature that behaviourally assessed short- and long-term cognitive function in individuals with a single mTBI, with the goal of identifying the impact of a single concussion on cognitive function in the chronic stage post-injury. CINAHL, Embase, and Medline/Ovid were searched July 2015 for studies related to concussion and cognitive impairment. Data relating to the presence/absence of cognitive impairment were extracted from 45 studies meeting our inclusion criteria. Results indicate that, in contrast to the prevailing view that most symptoms of concussion are resolved within 3 months post-injury, approximately half of individuals with a single mTBI demonstrate long-term cognitive impairment. Study limitations notwithstanding, these findings highlight the need to carefully examine the long-term implications of a single mTBI.
Asunto(s)
Conmoción Encefálica/complicaciones , Conmoción Encefálica/epidemiología , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/etiología , Conmoción Encefálica/psicología , Enfermedad Crónica , HumanosRESUMEN
CONTEXT: Deficiency of aromatase, the enzyme that catalyzes the conversion of androgens to estrogens, is associated with insulin resistance in humans and mice. OBJECTIVE: We hypothesized that pharmacological aromatase inhibition results in peripheral insulin resistance in humans. DESIGN: This was a double-blind, randomized, controlled, crossover study. SETTING: The study was conducted at a clinical research facility. PARTICIPANTS: Seventeen healthy male volunteers (18-50 y) participated in the study. INTERVENTION: The intervention included oral anastrozole (1 mg daily) and placebo, each for 6 weeks with a 2-week washout period. MAIN OUTCOME MEASURE: Glucose disposal and rates of lipolysis were measured during a stepwise hyperinsulinemic euglycemic clamp. Data are mean (SEM). RESULTS: Anastrozole therapy resulted in significant estradiol suppression (59.9 ± 3.6 vs 102.0 ± 5.7 pmol/L, P = < .001) and a more modest elevation of total T (25.8 ± 1.2 vs 21.4 ± 0.7 nmol/L, P = .003). Glucose infusion rate, during the low-dose insulin infusion, was lower after anastrozole administration (12.16 ± 1.33 vs 14.15 ± 1.55 µmol/kg·min, P = .024). No differences in hepatic glucose production or rate of lipolysis were observed. CONCLUSION: Aromatase inhibition reduces insulin sensitivity, with respect to peripheral glucose disposal, in healthy men. Local generation and action of estradiol, at the level of skeletal muscle, is likely to be an important determinant of insulin sensitivity.
Asunto(s)
Inhibidores de la Aromatasa/farmacología , Glucosa/metabolismo , Resistencia a la Insulina/fisiología , Lipólisis/efectos de los fármacos , Nitrilos/farmacología , Triazoles/farmacología , Adolescente , Adulto , Anastrozol , Estudios Cruzados , Método Doble Ciego , Estradiol/sangre , Técnica de Clampeo de la Glucosa , Voluntarios Sanos , Humanos , Hígado/efectos de los fármacos , Hígado/metabolismo , Masculino , Persona de Mediana Edad , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/metabolismo , Testosterona/sangre , Adulto JovenRESUMEN
OBJECTIVE: To determine which neurologic disorders/lesions impair or restrict motor imagery (MI) ability. DATA SOURCES: CINAHL, Cochrane, Embase, MEDLINE, Web of Science, PsychINFO, Physiotherapy Evidence Database, and Grey Literature were searched between May 8 and May 14, 2014. Keywords and Medical Subject Headings from 2 concepts (MI and lesion) were exploded to include related search terms (eg, mental practice/mental imagery, neurologic damage/lesion). STUDY SELECTION: Two independent reviewers assessed the 3861 studies that resulted from the database search. The studies were assessed for relevancy using the following inclusion criteria: use of explicit kinesthetic MI; neurologic lesion location identified; and use of an MI ability assessment tool. DATA EXTRACTION: Twenty-three studies encompassing 196 participants were included. The 23 studies used 8 different methods for assessing MI ability. MI assessment scores were then normalized to facilitate comparison across studies. DATA SYNTHESIS: Lesion locations comprised many brain areas, including cortical (eg, parietal and frontal lobes), subcortical (eg, basal ganglia, thalamus), and cerebellum. Lesion etiology primarily was comprised of stroke and Parkinson disease. Several participants presented with lesions resulting from other pathologies. Subjects with parietal lobe damage were most impaired on their ability to perform MI. Subjects with frontal lobe and basal ganglia damage also consistently showed impairment in MI ability. CONCLUSIONS: Subjects with damage to specific brain structures, including the parietal and frontal lobes, showed impaired MI ability. As such, MI-based neurorehabilitation may not be efficacious in all patient populations. Therefore, decisions related to the use of MI in neurorehabilitation should, in part, be based on the patient's underlying pathophysiology.
Asunto(s)
Encefalopatías/fisiopatología , Imágenes en Psicoterapia , Imaginación/fisiología , Corteza Motora/fisiopatología , Desempeño Psicomotor/fisiología , Humanos , Encuestas y CuestionariosRESUMEN
Leydig cell number and function decline as men age, and low testosterone is associated with all "Western" cardio-metabolic disorders. However, whether perturbed androgen action within the adult Leydig cell lineage predisposes individuals to this late-onset degeneration remains unknown. To address this, we generated a novel mouse model in which androgen receptor (AR) is ablated from â¼75% of adult Leydig stem cell/cell progenitors, from fetal life onward (Leydig cell AR knockout mice), permitting interrogation of the specific roles of autocrine Leydig cell AR signaling through comparison to adjacent AR-retaining Leydig cells, testes from littermate controls, and to human testes, including from patients with complete androgen insensitivity syndrome (CAIS). This revealed that autocrine AR signaling is dispensable for the attainment of final Leydig cell number but is essential for Leydig cell maturation and regulation of steroidogenic enzymes in adulthood. Furthermore, these studies reveal that autocrine AR signaling in Leydig cells protects against late-onset degeneration of the seminiferous epithelium in mice and inhibits Leydig cell apoptosis in both adult mice and patients with CAIS, possibly via opposing aberrant estrogen signaling. We conclude that autocrine androgen action within Leydig cells is essential for the lifelong support of spermatogenesis and the development and lifelong health of Leydig cells.
Asunto(s)
Síndrome de Resistencia Androgénica/patología , Andrógenos/farmacología , Apoptosis/efectos de los fármacos , Células Intersticiales del Testículo/patología , Receptores Androgénicos/fisiología , Testículo/patología , Adolescente , Adulto , Síndrome de Resistencia Androgénica/tratamiento farmacológico , Síndrome de Resistencia Androgénica/metabolismo , Animales , Comunicación Autocrina , Western Blotting , Células Cultivadas , Niño , Humanos , Técnicas para Inmunoenzimas , Células Intersticiales del Testículo/efectos de los fármacos , Células Intersticiales del Testículo/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Sustancias Protectoras/farmacología , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Espermatogénesis/efectos de los fármacos , Testículo/efectos de los fármacos , Testículo/metabolismo , Adulto JovenRESUMEN
Maternal obesity is linked with increased adverse pregnancy outcomes for both mother and child. The metabolic impact of excessive fat within the context of pregnancy is not fully understood. We used a mouse model of high fat (HF) feeding to induce maternal obesity to identify adipose tissue-mediated mechanisms driving metabolic dysfunction in pregnant and non-pregnant obese mice. As expected, chronic HF-feeding for 12 weeks preceding pregnancy increased peripheral (subcutaneous) and visceral (mesenteric) fat mass. However, unexpectedly at late gestation (E18.5) HF-fed mice exhibited a remarkable normalization of visceral but not peripheral adiposity, with a 53% reduction in non-pregnant visceral fat mass expressed as a proportion of body weight (P<0.001). In contrast, in control animals, pregnancy had no effect on visceral fat mass proportion. Obesity exaggerated glucose intolerance at mid-pregnancy (E14.5). However by E18.5, there were no differences, in glucose tolerance between obese and control mice. Transcriptomic analysis of visceral fat from HF-fed dams at E18.5 revealed reduced expression of genes involved in de novo lipogenesis (diacylglycerol O-acyltransferase 2--Dgat2) and inflammation (chemokine C-C motif ligand 20--Ccl2) and upregulation of estrogen receptor α (ERα) compared to HF non pregnant. Attenuation of adipose inflammation was functionally confirmed by a 45% reduction of CD11b+CD11c+ adipose tissue macrophages (expressed as a proportion of all stromal vascular fraction cells) in HF pregnant compared to HF non pregnant animals (P<0.001). An ERα selective agonist suppressed both de novo lipogenesis and expression of lipogenic genes in adipocytes in vitro. These data show that, in a HF model of maternal obesity, late gestation is associated with amelioration of visceral fat hypertrophy, inflammation and glucose intolerance, and suggest that these effects are mediated in part by elevated visceral adipocyte ERα signaling.
Asunto(s)
Adipocitos/citología , Adiposidad , Estrógenos/metabolismo , Grasa Intraabdominal/metabolismo , Ratones Obesos , Adipocitos/metabolismo , Animales , Femenino , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Análisis de Secuencia por Matrices de Oligonucleótidos , Embarazo , Preñez , Receptores de Estrógenos/metabolismo , Transducción de Señal , Factores de Tiempo , TranscriptomaRESUMEN
OBJECTIVE: 11ß-Hydroxysteroid dehydrogenase type I (11ßHSD1) regenerates active cortisol from inert cortisone in adipose tissue. Elevated adipose tissue 11ßHSD1 activity is observed in obese humans and rodents, where it is linked to obesity and its metabolic consequences. Menopause is also associated with increased abdominal fat accumulation, suggesting that estrogen is also important in adipose tissue metabolism. The purpose of this current study was to establish whether estrogen signaling through estrogen receptor α (ER-α) and estrogen receptor ß (ER-ß) could influence 11ßHSD1 in premenopausal and postmenopausal adipose tissues. METHODS: Nineteen premenopausal (aged 26 ± 5 y; body mass index, 23.6 ± 1.6 kg/m) and 23 postmenopausal (aged 63 ± 4 y; body mass index, 23.4 ± 1.9 kg/m) healthy women were studied. Subcutaneous adipose tissue biopsies and fasting venous blood samples were taken. Body composition was measured by bioelectrical impedance analysis. Human Simpson-Golabi-Behmel syndrome adipocyte cells were treated with ER-α- and ER-ß-specific agonists for 24 hours. Basic anthropometric data, serum 17ß-estradiol and progesterone concentrations, ER-α and ER-ß messenger RNA (mRNA) levels, and 11ßHSD1 mRNA, protein, and activity levels were assessed. RESULTS: ER-ß and 11ßHSD1, but not ER-α, mRNAs were significantly increased in adipose tissue from postmenopausal women compared with premenopausal women. ER-ß had a significant positive correlation with the mRNA level of 11ßHSD1 in adipose tissue from premenopausal and postmenopausal women. This association between ER-ß and 11ßHSD1 was greatest in adipose tissue from postmenopausal women. In human Simpson-Golabi-Behmel syndrome adipocytes, diarylpropiolnitrile, a selective ER-ß agonist, increased 11ßHSD1 mRNA, protein, and activity levels. CONCLUSIONS: We conclude that, in adipose tissue, ER-ß-mediated estrogen signaling can up-regulate 11ßHSD1 and that this may be of particular importance in postmenopausal women.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasas/genética , 11-beta-Hidroxiesteroide Deshidrogenasas/metabolismo , Tejido Adiposo/química , Tejido Adiposo/enzimología , Receptor beta de Estrógeno/análisis , Posmenopausia/metabolismo , Adulto , Composición Corporal , Estradiol/sangre , Receptor alfa de Estrógeno/análisis , Receptor alfa de Estrógeno/genética , Receptor beta de Estrógeno/genética , Receptor beta de Estrógeno/fisiología , Estrógenos/fisiología , Femenino , Humanos , Persona de Mediana Edad , Premenopausia/metabolismo , Progesterona/sangre , ARN Mensajero/análisis , Transducción de Señal/fisiología , Regulación hacia ArribaRESUMEN
Testosterone deficiency is epidemic in obese ageing males with type 2 diabetes, but the direction of causality remains unclear. Testosterone-deficient males and global androgen receptor (AR) knockout mice are insulin resistant with increased fat, but it is unclear whether AR signaling in adipose tissue mediates body fat redistribution and alters glucose homoeostasis. To investigate this, mice with selective knockdown of AR in adipocytes (fARKO) were generated. Male fARKO mice on normal diet had reduced perigonadal fat but were hyperinsulinemic and by age 12 months, were insulin deficient in the absence of obesity. On high-fat diet, fARKO mice had impaired compensatory insulin secretion and hyperglycemia, with increased susceptibility to visceral obesity. Adipokine screening in fARKO mice revealed a selective increase in plasma and intra-adipose retinol binding protein 4 (RBP4) that preceded obesity. AR activation in murine 3T3 adipocytes downregulated RBP4 mRNA. We conclude that AR signaling in adipocytes not only protects against high-fat diet-induced visceral obesity but also regulates insulin action and glucose homeostasis, independently of adiposity. Androgen deficiency in adipocytes in mice resembles human type 2 diabetes, with early insulin resistance and evolving insulin deficiency.
Asunto(s)
Tejido Adiposo/metabolismo , Glucosa/metabolismo , Homeostasis/fisiología , Receptores Androgénicos/metabolismo , Proteínas Plasmáticas de Unión al Retinol/metabolismo , Adipoquinas/genética , Adipoquinas/metabolismo , Animales , Glucemia , Grasas de la Dieta/efectos adversos , Glucosa/administración & dosificación , Glucosa/farmacocinética , Intolerancia a la Glucosa , Humanos , Insulina/metabolismo , Proteínas Sustrato del Receptor de Insulina/genética , Proteínas Sustrato del Receptor de Insulina/metabolismo , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Receptores Androgénicos/genética , Proteínas Plasmáticas de Unión al Retinol/genética , Transducción de Señal , Testosterona/metabolismoRESUMEN
The liver kinase B1 (LKB1) is encoded by the STK11 gene and acts as a tumour suppressor and a regulator of energy homeostasis. LKB1 expression is reduced in primary breast tumours compared to normal breast epithelium. Although its expression in primary tumours does not appear to correlate with estrogen receptor (ER) status, it is differentially expressed in breast cancer cell lines where ER-negative cells have lower LKB1 expression than ER-positive cells. The present study aimed to examine the effects of estradiol on LKB1 expression and activity in the ER-positive breast cancer cell line MCF-7. Results demonstrate that estradiol causes a dose-dependent decrease in LKB1 transcript and protein expression and consistent with this, a significant decrease in the phosphorylation of the LKB1 target AMPK (P ≤ 0.05). In order to assess whether effects of estradiol were due to effects on ERα binding to the STK11 promoter, ChIP was performed. Results demonstrate that ERα binds to the STK11 promoter in a ligand-independent manner and that this interaction is decreased in the presence of estradiol. Moreover, STK11 promoter activity is significantly decreased in the presence of estradiol (P ≤ 0.05). LKB1 transcript and IHC score were assessed in primary tumours of 18 patients and demonstrated no significant correlation with ER status (n = 18). Our results thereby provide a mechanism whereby LKB1 is decreased in ER-positive breast tumours.
Asunto(s)
Estradiol/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/genética , Quinasas de la Proteína-Quinasa Activada por el AMP , Secuencia de Bases , Western Blotting , Línea Celular Tumoral , Inmunoprecipitación de Cromatina , Cartilla de ADN , Relación Dosis-Respuesta a Droga , Humanos , Persona de Mediana Edad , Fosforilación , Regiones Promotoras Genéticas , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
The association between low birth weight and cardiovascular disease is amplified by the development of obesity. We explored the effects of postnatal high-fat (HF) feeding in dexamethasone (Dex)-programmed rats, in which prenatal glucocorticoid overexposure is associated with reduced birth weight and adult glucose intolerance. Male Wistar rats exposed to Dex or vehicle (Veh) during the last week of gestation were weaned onto HF or control diets for 6 months. Dex-exposed animals were of lower birth weight and showed catch-up growth by 7 wk. There were no differences in obesity or hyperinsulinaemia between Dex-HF and Veh-HF animals. However, Dex-HF animals had increased hepatic triglyceride content compared with Veh-HF animals. mRNA transcript profiles in adipose tissue revealed depot-specific changes in the expression of genes involved in fatty acid esterification and triglyceride synthesis and storage with prenatal Dex exposure. Thus, antenatal glucocorticoid overexposure in rats does not confer increased sensitivity to HF diet-induced obesity, but increases susceptibility to fatty liver. This may be due to depot-specific-programmed alterations in fat metabolism in adipose tissue.
Asunto(s)
Tejido Adiposo/metabolismo , Dexametasona/administración & dosificación , Regulación de la Expresión Génica/genética , Hígado/metabolismo , Obesidad/metabolismo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Triglicéridos/metabolismo , Proteínas Quinasas Activadas por AMP/genética , Proteínas Quinasas Activadas por AMP/metabolismo , Tejido Adiposo/efectos de los fármacos , Análisis de Varianza , Animales , Animales Recién Nacidos , Peso al Nacer/efectos de los fármacos , Peso al Nacer/genética , Glucemia/genética , Glucemia/metabolismo , Western Blotting , Hígado Graso/genética , Hígado Graso/metabolismo , Femenino , Glucocorticoides/administración & dosificación , Prueba de Tolerancia a la Glucosa , Insulina/sangre , Hígado/efectos de los fármacos , Masculino , Obesidad/genética , Tamaño de los Órganos/efectos de los fármacos , Tamaño de los Órganos/genética , Fosforilación , Embarazo , Efectos Tardíos de la Exposición Prenatal/genética , Ratas , Ratas Wistar , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Epidemiologic evidence supports a correlation between obesity and breast cancer in women. AMP-activated protein kinase plays an important role in energy homeostasis and inhibits the actions of cyclic AMP-responsive element binding protein-regulated transcription coactivator 2 (CRTC2). In postmenopausal women, the cyclic AMP-responsive element binding protein-dependent regulation of aromatase is a determinant of breast tumor formation through local production of estrogens. The present work aimed to examine the effect of adipokines on aromatase expression and identify additional mechanisms by which prostaglandin E(2) causes increased aromatase expression in human breast adipose stromal cells. Treatment of human adipose stromal cells with forskolin and phorbol 12-myristate 13-acetate (PMA), to mimic prostaglandin E(2), resulted in nuclear translocation of CRTC2. Aromatase promoter II (PII) activity assays showed that CRTC2 in addition to forskolin/PMA treatment significantly increased PII-induced activity. CRTC2 binding to PII was examined by chromatin immunoprecipitation, and forskolin/PMA treatment was associated with increased binding to PII. Treatment of human adipose stromal cells with leptin significantly up-regulated aromatase expression associated with nuclear translocation of CRTC2 and increased binding of CRTC2 to PII. Adiponectin treatment significantly decreased forskolin/PMA-stimulated aromatase expression, consistent with the decreased nuclear translocation of CRTC2 and the decreased binding of CRTC2 to PII. The expression and activity of the AMP-activated protein kinase LKB1 was examined and found to be significantly decreased following either forskolin/PMA or leptin treatment. In contrast, adiponectin significantly increased LKB1 expression and activity. In conclusion, the regulation of aromatase by CRTC2, in response to the altered hormonal milieu associated with menopause and obesity, provides a critical link between obesity and breast cancer.
Asunto(s)
Neoplasias de la Mama/epidemiología , Obesidad/epidemiología , Posmenopausia , Factores de Transcripción/fisiología , Aromatasa/genética , Aromatasa/metabolismo , Colforsina/farmacología , Cartilla de ADN , Estradiol/fisiología , Estrógenos/fisiología , Femenino , Genes Reporteros , Homeostasis , Humanos , Leptina/uso terapéutico , Mamoplastia , Obesidad/complicaciones , Reacción en Cadena de la Polimerasa , Mapeo Restrictivo , Células del Estroma/citología , Células del Estroma/fisiología , Acetato de Tetradecanoilforbol/farmacología , Factores de Transcripción/genética , TransfecciónRESUMEN
UNLABELLED: 17beta-Estradiol, the most potent circulating estrogen, has been shown to greatly impact on the development and formation of tissues of the urogenital tract. The adult kidney has previously been shown to be highly responsive to 17beta-estradiol stimulation. However, the direct effect of 17beta-estradiol on kidney development remains unclear. AIM: To investigate the direct effect of 17beta-estradiol on male and female metanephric kidney development. METHODS: Whole embryonic-day-12.5 (E12.5) C57Bl/6 male and female mouse metanephroi were cultured in the presence of varying concentrations of 17beta-estradiol (0.1-5.0 nM) for 72 h. Metanephric development was assessed using immunofluorescence labeling techniques. The real-time polymerase chain reaction was used to investigate estrogen receptor-alpha (ERalpha), glial-cell-line-derived neurotrophic factor (GDNF) and its associated receptor cRET, transforming growth factor-beta (TGFbeta1), TGFbeta2 and TGFbeta3 mRNA expression levels. RESULTS: ERalpha was present in developing metanephroi at E12.5; however, ERbeta was absent. No significant sex difference in ERalpha mRNA expression was observed. Significant increases in the number of ureteric branch points, terminal tips and developing glomeruli were observed in female metanephroi cultured in the presence of 1.0 and 5.0 nM 17beta-estradiol. Conversely, no significant effect was observed in male metanephroi cultured with 17beta-estradiol. GDNF and cRET mRNA expression was increased in both male and female metanephroi, whilst TGFbeta1 and TGFbeta2 mRNA expression was decreased following culture in the presence of 17beta-estradiol. CONCLUSION: This study is the first to establish that the mouse metanephros displays a sexual dimorphism in response to specific concentrations of estrogens.
Asunto(s)
Estradiol/administración & dosificación , Riñón/efectos de los fármacos , Riñón/crecimiento & desarrollo , Caracteres Sexuales , Animales , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Técnicas de Cultivo de Órganos , EmbarazoRESUMEN
With the growing incidence of HIV, there is a desperate need to develop simple, cheap and effective new ways of preventing HIV infection. Male circumcision reduces the risk of infection by about 60%, probably because of the removal of the Langerhans cells which are abundant in the inner foreskin and are the primary route by which HIV enters the penis. Langerhans cells form a vital part of the body's natural defence against HIV and only cause infection when they are exposed to high levels of HIV virions. Rather than removing this natural defence mechanism by circumcision, it may be better to enhance it by thickening the layer of keratin overlying the Langerhans cells, thereby reducing the viral load to which they are exposed. We have investigated the ability of topically administered oestrogen to induce keratinization of the epithelium of the inner foreskin. Histochemically, the whole of the foreskin is richly supplied with oestrogen receptors. The epithelium of the inner foreskin, like the vagina, responds within 24 hours to the topical administration of oestriol by keratinization, and the response persists for at least 5 days after the cessation of the treatment. Oestriol, a cheap, readily available natural oestrogen metabolite, rapidly keratinizes the inner foreskin, the site of HIV entry into the penis. This thickening of the overlying protective layer of keratin should reduce the exposure of the underlying Langerhans cells to HIV virions. This simple treatment could become an adjunct or alternative to surgical circumcision for reducing the incidence of HIV infection in men.
Asunto(s)
Estrógenos/administración & dosificación , Prepucio/metabolismo , Infecciones por VIH/prevención & control , Administración Tópica , Secuencia de Bases , Circuncisión Masculina , Cartilla de ADN , Receptor alfa de Estrógeno/genética , Receptor beta de Estrógeno/genética , Infecciones por VIH/patología , Humanos , Inmunohistoquímica , Masculino , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Aromatase is a member of the cytochrome P450 superfamily of enzymes which catalyses the rate-limiting step in the biosynthesis of estrogens. A number of clinical studies have highlighted the importance of local estrogen production in adipose tissue. In particular, in the postmenopausal woman, the degree of her estrogenization is mainly determined by the extent of her adiposity and it is this extragonadal source of estrogen that likely contributes to breast cancer development and progression. The mechanisms regulating aromatase expression in adipose tissue however, have not been fully elucidated. In this study, we have characterised the expression of aromatase and its activity in a human preadipocyte cell strain, SGBS. Aromatase is expressed in SGBS cells and its expression and activity are strongly stimulated by forskolin (FSK) and phorbol 12-myristate-13-acetate (PMA) treatment. Consistent with this, FSK and PMA treatment also increased activation of the proximal aromatase promoter, promoter II. These findings mimic those that have previously been shown in isolated primary human preadipocytes. These data suggest that SGBS cells are a valuable model with which to further elucidate the mechanisms regulating aromatase expression, and therefore local estrogen synthesis in human adipose tissue.
Asunto(s)
Adipocitos/enzimología , Aromatasa/biosíntesis , Adipocitos/metabolismo , Tejido Adiposo/metabolismo , Aromatasa/metabolismo , Línea Celular , Colforsina/farmacología , Sistema Enzimático del Citocromo P-450/metabolismo , ADN Complementario/metabolismo , Progresión de la Enfermedad , Estrógenos/metabolismo , Humanos , Regiones Promotoras Genéticas , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Acetato de Tetradecanoilforbol/farmacología , Factores de TiempoRESUMEN
Aromatase deficiency is rare in humans. Affected individuals cannot synthesize endogenous estrogens. Aromatase is the enzyme that catalyzes conversion of androgens into estrogens, and if aromatase is nonfunctional because of an inactivating mutation, estrogen synthesis cannot occur. If the fetus lacks aromatase activity, dehydroepiandrosterone sulfate produced by the fetal adrenal glands cannot be converted to estrogen by the placenta, so is converted to testosterone peripherally and results in virilization of both fetus and mother. Virilization manifests as pseudohermaphroditism in female infants, with hirsutism and acne in the mother; the maternal indicators resolve following delivery. To date, only seven males and seven females with aromatase deficiency have been reported. Affected females are typically diagnosed at birth because of the pseudohermaphroditism. Cystic ovaries and delayed bone maturation can occur during childhood and adolescence in these girls, who present at puberty with primary amenorrhea, failure of breast development, virilization, and hypergonadotrophic hypogonadism. Affected males, on the other hand, do not present with obvious defects at birth, so are diagnosed much later in life, presenting with clinical symptoms, which include tall stature, delayed skeletal maturation, delayed epiphyseal closure, bone pain, eunuchoid body proportions and excess adiposity. Estrogen replacement therapy reverses the symptoms in male and female patients.
Asunto(s)
Aromatasa/deficiencia , Adiposidad/fisiología , Adolescente , Adulto , Aromatasa/genética , Huesos/metabolismo , Terapia de Reemplazo de Estrógeno , Estrógenos/uso terapéutico , Femenino , Hormonas/uso terapéutico , Humanos , Infertilidad Masculina/metabolismo , Resistencia a la Insulina/fisiología , Masculino , Errores Innatos del Metabolismo/diagnóstico , Errores Innatos del Metabolismo/genética , Errores Innatos del Metabolismo/terapia , Mutación , Embarazo , Factores SexualesRESUMEN
BACKGROUND: Aromatase converts androgen to estrogen. Thus, the aromatase knockout (ArKO) mouse is estrogen deficient. We investigated the compulsive behaviors of these animals and the protein levels of catechol-O-methyltransferase (COMT) in frontal cortex, hypothalamus and liver. METHODS: Grooming was analyzed during the 20-min period immediately following a water-mist spray. Running wheel activity over two consecutive nights and barbering were analyzed. COMT protein levels were measured by Western analysis. RESULTS: Six-month old male but not female ArKO mice develop compulsive behaviors such as excessive barbering, grooming and wheel-running. Excessive activities were reversed by 3 weeks of 17beta-estradiol replacement. Interestingly, the presentation of compulsive behaviors is accompanied by concomitant decreases (p < .05) in hypothalamic COMT protein levels in male ArKO mice. These values returned to normal upon 17beta-estradiol treatment. In contrast, hepatic and frontal cortex COMT levels were not affected by the estrogen status, indicating region- and tissue-specific regulation of COMT levels by estrogen. No differences in COMT levels were detectable between female animals of both genotypes. CONCLUSIONS: This study describes the novel observation of a possible link between estrogen, COMT and development of compulsive behaviors in male animals which may have therapeutic implications in obsessive compulsive disorder (OCD) patients.
Asunto(s)
Conducta Compulsiva/fisiopatología , Conducta Compulsiva/psicología , Estrógenos/deficiencia , Animales , Aromatasa/genética , Aromatasa/fisiología , Western Blotting , Encéfalo/enzimología , Catecol O-Metiltransferasa/genética , Catecol O-Metiltransferasa/metabolismo , Conducta Compulsiva/genética , Estradiol/farmacología , Estrógenos/farmacología , Femenino , Aseo Animal/fisiología , Hígado/enzimología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Actividad Motora/fisiologíaRESUMEN
Menopause is associated with an accumulation of visceral fat. An emerging concept suggests that relatively elevated levels of circulating androgens, compared with estrogens in postmenopausal women, underlie this shift in body fat distribution. In this study we administered dihydrotestosterone (DHT) to ovariectomized mice to examine the effect of relative androgen excess on adipose tissue distribution and function in estrogen-deficient mice. Compared with controls, DHT-treated mice exhibited increased body weight and visceral fat mass associated with triglyceride accumulation. Phosphorylation of AMP-activated protein kinase (AMPK) and acetyl CoA carboxylase was significantly decreased by DHT in visceral fat. In 3T3-L1 cells, DHT decreased phosphorylation of AMPK in a dose-dependent manner. In addition, DHT increased the expression of lipogenic genes (fatty acid synthase, sterol regulatory element binding protein-2, and lipoprotein lipase) in visceral fat. These data provide the first in vivo evidence that an increased androgen to estrogen ratio can promote visceral fat accumulation by inhibiting AMPK activation and stimulating lipogenesis.
Asunto(s)
Andrógenos/farmacología , Estrógenos/deficiencia , Grasa Intraabdominal/efectos de los fármacos , Lipogénesis/efectos de los fármacos , Complejos Multienzimáticos/metabolismo , Obesidad/etiología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Quinasas Activadas por AMP , Acetil-CoA Carboxilasa/metabolismo , Adipogénesis/efectos de los fármacos , Adipogénesis/genética , Tejido Adiposo/efectos de los fármacos , Animales , Peso Corporal/efectos de los fármacos , Dihidrotestosterona/farmacología , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ovariectomía/efectos adversos , Fosforilación/efectos de los fármacos , Triglicéridos/biosíntesisAsunto(s)
Tejido Adiposo/metabolismo , Estradiol/metabolismo , Adenilato Quinasa/metabolismo , Tejido Adiposo/patología , Animales , Estrógenos/metabolismo , Ácidos Grasos/metabolismo , Femenino , Homeostasis , Humanos , Metabolismo de los Lípidos , Masculino , Ratones , Modelos Biológicos , Músculos/metabolismo , Músculos/patología , Mutación , Oxígeno/metabolismo , Procesos de Determinación del Sexo , Factores de TiempoRESUMEN
OBJECTIVE: Obesity is associated with altered glucocorticoid metabolism, which may impact on hypothalamic-pituitary-adrenal axis activity. Here we characterize hepatic 5alpha- and 5beta-reductase in obese rats and their responses to insulin sensitization. RESEARCH METHODS AND PROCEDURES: Hepatic A-ring reductase protein and mRNA were assessed in lean and obese Zucker rats after insulin sensitization with metformin or rosiglitazone (n = 7 to 8/group). RESULTS: Hepatic 5alpha-reductase 1 and 5beta-reductase mRNA and protein (p < 0.01) were increased in obese rats. Insulin sensitization ameliorated increased 5alpha-reductase 1 mRNA in obese rats (p < 0.01) and partially reversed increased 5beta-reductase activity. DISCUSSION: Hepatic clearance of glucocorticoids by 5alpha- and 5beta-reductase is increased in obese Zucker rats, and this increase in clearance is attenuated by insulin sensitization. This increased hepatic clearance may underpin compensatory activation of the hypothalamic-pituitary-adrenal axis in obesity.