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1.
Artigo em Inglês | MEDLINE | ID: mdl-33522399

RESUMO

Studies in humans and rodents show that probiotic bacteria can protect from bone loss caused by sex-steroid deficiency. We showed earlier that a mixture of three probiotic bacteria, Lacticaseibacillus paracasei DSM13434, Lactiplantibacillus plantarum DSM 15312 and DSM 15313 (L. Mix) protects mice from ovariectomy (ovx)-induced bone loss when treatment was started two weeks before sham and ovx surgery. In addition, the same probiotic treatment protected against lumbar spine bone loss in early postmenopausal women. In the present study we wanted to evaluate the therapeutic potential of L. Mix by starting treatment 1.5 weeks after ovx when most of the rapid bone loss as a result of estrogen deficiency, has already occurred. Treatment with L. Mix for 5.5 weeks increased the trabecular thickness but not the trabecular number in the proximal metaphyseal region of tibia compared to vehicle treatment. Cortical thickness and cortical area of the mid-diaphyseal part of tibia were decreased in the vehicle-treated ovx mice but not in L. Mix-treated ovx mice compared to sham mice. The bone protective effects of L. Mix in ovx mice were associated with a protection against ovx-induced reduction of the frequency of regulatory T-cells and of the expression of Tgfß in the bone marrow. In conclusion, the probiotic L. Mix exerted a moderate stimulatory effect on trabecular and cortical bone width when treatment is initiated 1.5 weeks after ovariectomy in mice. This effect was associated with effects on bone protecting regulatory T-cells. The results suggest that L. Mix may exert beneficial effects on bone mass when treatment is started after ovariectomy.

2.
Genome Med ; 13(1): 16, 2021 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-33536041

RESUMO

BACKGROUND: Accurately quantifying the risk of osteoporotic fracture is important for directing appropriate clinical interventions. While skeletal measures such as heel quantitative speed of sound (SOS) and dual-energy X-ray absorptiometry bone mineral density are able to predict the risk of osteoporotic fracture, the utility of such measurements is subject to the availability of equipment and human resources. Using data from 341,449 individuals of white British ancestry, we previously developed a genome-wide polygenic risk score (PRS), called gSOS, that captured 25.0% of the total variance in SOS. Here, we test whether gSOS can improve fracture risk prediction. METHODS: We examined the predictive power of gSOS in five genome-wide genotyped cohorts, including 90,172 individuals of European ancestry and 25,034 individuals of Asian ancestry. We calculated gSOS for each individual and tested for the association between gSOS and incident major osteoporotic fracture and hip fracture. We tested whether adding gSOS to the risk prediction models had added value over models using other commonly used clinical risk factors. RESULTS: A standard deviation decrease in gSOS was associated with an increased odds of incident major osteoporotic fracture in populations of European ancestry, with odds ratios ranging from 1.35 to 1.46 in four cohorts. It was also associated with a 1.26-fold (95% confidence interval (CI) 1.13-1.41) increased odds of incident major osteoporotic fracture in the Asian population. We demonstrated that gSOS was more predictive of incident major osteoporotic fracture (area under the receiver operating characteristic curve (AUROC) = 0.734; 95% CI 0.727-0.740) and incident hip fracture (AUROC = 0.798; 95% CI 0.791-0.805) than most traditional clinical risk factors, including prior fracture, use of corticosteroids, rheumatoid arthritis, and smoking. We also showed that adding gSOS to the Fracture Risk Assessment Tool (FRAX) could refine the risk prediction with a positive net reclassification index ranging from 0.024 to 0.072. CONCLUSIONS: We generated and validated a PRS for SOS which was associated with the risk of fracture. This score was more strongly associated with the risk of fracture than many clinical risk factors and provided an improvement in risk prediction. gSOS should be explored as a tool to improve risk stratification to identify individuals at high risk of fracture.

3.
J Hum Genet ; 2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33469137

RESUMO

The stress hormone cortisol modulates fuel metabolism, cardiovascular homoeostasis, mood, inflammation and cognition. The CORtisol NETwork (CORNET) consortium previously identified a single locus associated with morning plasma cortisol. Identifying additional genetic variants that explain more of the variance in cortisol could provide new insights into cortisol biology and provide statistical power to test the causative role of cortisol in common diseases. The CORNET consortium extended its genome-wide association meta-analysis for morning plasma cortisol from 12,597 to 25,314 subjects and from ~2.2 M to ~7 M SNPs, in 17 population-based cohorts of European ancestries. We confirmed the genetic association with SERPINA6/SERPINA1. This locus contains genes encoding corticosteroid binding globulin (CBG) and α1-antitrypsin. Expression quantitative trait loci (eQTL) analyses undertaken in the STARNET cohort of 600 individuals showed that specific genetic variants within the SERPINA6/SERPINA1 locus influence expression of SERPINA6 rather than SERPINA1 in the liver. Moreover, trans-eQTL analysis demonstrated effects on adipose tissue gene expression, suggesting that variations in CBG levels have an effect on delivery of cortisol to peripheral tissues. Two-sample Mendelian randomisation analyses provided evidence that each genetically-determined standard deviation (SD) increase in morning plasma cortisol was associated with increased odds of chronic ischaemic heart disease (0.32, 95% CI 0.06-0.59) and myocardial infarction (0.21, 95% CI 0.00-0.43) in UK Biobank and similarly in CARDIoGRAMplusC4D. These findings reveal a causative pathway for CBG in determining cortisol action in peripheral tissues and thereby contributing to the aetiology of cardiovascular disease.

4.
Bone ; : 115792, 2020 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-33285254

RESUMO

OBJECTIVE: Hip shape is a well-recognized risk factor for hip osteoarthritis (OA) and hip fracture. We aimed to investigate whether the genetic variants known to be associated with adult hip shape were also associated with adolescent hip shape. METHODS: Hip DXA scans, obtained in offspring from the Avon Longitudinal Study of Parents and Children (ALSPAC) at two time points (mean ages 13.8 and 17.8 years), were used to quantify hip morphology using a 53-point Statistical Shape Model (SSM). Principal component analysis was used to generate hip shape modes (HSMs). Genetic variants which had previously shown genome-wide significant association with specific HSMs in adults were tested for association with the same HSMs in adolescents (at each timepoint separately) using SNPTEST v2. RESULTS: Complete genotypic and phenotypic data were available for 3,550 and 3,175 individuals at 14 and 18 years, respectively. The strongest evidence for association with adolescent hip shape was for a variant located near SOX9 (rs2158915) with consistent effects across both time points for HSM1 (age 14: beta -0.05, p=9.9 x10-8; age 18: -0.05, p=3.3 x10-6) and HSM5 (age 14: beta -0.07, p=1.6 x10-4; age 18: -0.1, p=2.7 x10-6). There was also strong evidence of association between rs10743612 (near PTHLH) and HSM1 (age 14: 0.05, p=1.1 x10-5; age 18: 0.04, p=0.003) and between rs6537291 (near HHIP) and HSM2 (age 14: -0.06, p=0.001; age 18: -0.07, p=0.001) across both time points. The genes with the strongest associations with hip shape in adolescents, (SOX9, PTHLH and HHIP) are known to be involved in endochondral bone formation. HSM1 indicates narrower aspect ratio of the upper femur, whereas both HSM2 and HSM5 reflect variation in the femoral head size and femoral neck width, features previously found to be related to the risk of OA in later life. The SOX9 locus has previously been found to associate with increased risk of hip fracture. CONCLUSION: In conclusion, variants implicated in endochondral bone formation appear to consistently influence hip shape between adolescence and adulthood, including those aspects related to risk of hip OA and/or fracture in later life.

5.
Artigo em Inglês | MEDLINE | ID: mdl-33225718

RESUMO

Estrogen protects against bone loss, but is not a suitable treatment due to adverse effects in other tissues. Increased knowledge regarding estrogen signaling in estrogen-responsive tissues is therefore warranted to aid the development of bone-specific estrogen treatments. Estrogen receptor alpha (ERα), the main mediator of estrogenic effects in bone, is widely subjected to posttranslational modifications (PTMs). In vitro studies have shown that methylation at site R260 in the human ERα affects receptor localization and intracellular signaling. The corresponding amino acid R264 in murine ERα has been shown to have a functional role in endothelium in vivo; albeit the methylation of R264 in the murine gene is yet to be empirically demonstrated. The aim of this study was to investigate if R264 in ERα is involved in the regulation of the skeleton in vivo. DXA analysis at three, six, nine, and twelve months of age showed no differences in total body areal BMD between R264A and WT in either female or male mice. Furthermore, analyses using CT demonstrated that trabecular bone mass in tibia and vertebra, and cortical thickness in tibia, were similar between R264A and WT mice. In addition, R264A females displayed a normal estrogen treatment response in trabecular bone mass, as well as in cortical thickness. Furthermore, uterus, thymus, and adipose tissue responded similarly in R264A and WT female mice after estrogen treatment. In conclusion, our novel finding that mutation of R264 in ERα does not affect the regulation of the skeleton, together with the known role of R264 for ERα-mediated endothelial effects, supports the concept that R264 determines tissue specificity of ERα.

6.
Am J Clin Nutr ; 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33184646

RESUMO

BACKGROUND: Recent findings indicate that there is a body weight-sensing homeostatic regulation of body weight in postpubertal rodents and humans. It is possible that body weight sensing also might be involved in the regulation of pubertal timing. Although an early small study suggested that there is a critical body weight for pubertal timing in girls, most studies have focused on BMI and reported an inverse association between BMI and pubertal timing. OBJECTIVES: In the present longitudinal well-powered cohort study, we revisited the critical weight hypothesis and tested if prepubertal body weight is a more robust inverse predictor of pubertal timing than prepubertal BMI in boys. METHOD: We included men born during 1945-1961 (old cohort; n = 31,971) and men born during 1981-1996 (recent cohort; n = 1465) in the large BMI Epidemiology Study (BEST) Gothenburg (combined BEST cohort n = 33,436). Men with information on prepubertal body weight and BMI at 8 y of age and age at peak height velocity (PHV; an objective measure of pubertal timing) were included. RESULTS: Body weight explained more of the variance in age at PHV than BMI in both the old cohort and the recent cohort (combined cohort, body weight 6.3%, BMI 3.6%). Both body weight (ß: -0.24 SD/SD increase in weight; 95% CI: -0.25, -0.23) and BMI (ß: -0.18 SD/SD increase in BMI, 95% CI: -0.19, -0.17) were inversely associated with age at PHV but the association for body weight was significantly more pronounced than the association for BMI (P < 0.001). CONCLUSIONS: In conclusion, prepubertal body weight is a more robust inverse predictor of pubertal timing than prepubertal BMI in boys. We propose that body weight sensing constitutes a feedback mechanism to regulate pubertal timing.

7.
Bone ; : 115768, 2020 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-33232837

RESUMO

It is well known that high-level exposure to cadmium can cause bone disease such as osteoporosis, osteomalacia and fractures. However, the effect of low-level exposure, as found in the general population (mainly derived from diet and smoking), has only been assessed recently. The aim of this study was to examine if cadmium exposure in the general Swedish population causes other bone changes than decreased areal bone mineral density as measured by traditional DXA technology, e.g. changes in microstructure and geometry, such as cortical thickness or area, cortical porosity and trabecular bone volume. The study population consisted of 444 men, aged 70-81 years at inclusion year 2002-2004, from the Swedish cohort of the Osteoporotic Fractures in Men Study (MrOS). Cadmium was analyzed in baseline urine samples (UCd). Different parameters of bone geometry and microstructure were measured at the distal tibia at follow-up in 2009, including examination with high-resolution peripheral quantitative computed tomography (HR-pQCT). Associations between bone parameters and UCd in tertiles were estimated in multivariable analyses, including potential confounding factors (age, smoking, BMI, and physical activity). We found significant associations between UCd and several bone geometry or microstructure parameters, with 9% lower cortical thickness (p = 0.03), 7% lower cortical area (p = 0.04), and 5% lower trabecular bone volume fraction (p = 0.02) in the third tertile of UCd, using the first tertile as the reference. Furthermore, significant negative associations were found between log-transformed UCd and cortical thickness, cortical area, trabecular number and trabecular bone volume fraction, and a significant positive association with trabecular separation. The results indicate that low-level Cd exposure in the general population has negative effects on both cortical and trabecular bone.

9.
Aging (Albany NY) ; 12(20): 19979-20000, 2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-33107844

RESUMO

Aging is associated with a decline in sex hormones, variable between sexes, that has an impact on many different body systems and might contribute to age-related disease progression. We aimed to characterize the sex differences in gut microbiota, and to explore the impact of depletion of gonadal hormones, alone or combined with postnatal overfeeding, in rats. Many of the differences in the gut microbiota between sexes persisted after gonadectomy, but removal of gonadal hormones shaped several gut microbiota features towards a more deleterious profile, the effect being greater in females than in males, mainly when animals were concurrently overfed. Moreover, we identified several intestinal miRNAs as potential mediators of the impact of changes in gut microbiota on host organism physiology. Our study points out that gonadal hormones contribute to defining sex-dependent differences of gut microbiota, and discloses a potential role of gonadal hormones in shaping gut microbiota, as consequence of the interaction between sex and nutrition. Our data suggest that the changes in gut microbiota, observed in conditions of sex hormone decline, as those caused by ageing in men and menopause in women, might exert different effects on the host organism, which are putatively mediated by gut microbiota-intestinal miRNA cross-talk.

10.
EClinicalMedicine ; 27: 100530, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33033795
11.
FASEB J ; 34(12): 15991-16002, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33067917

RESUMO

Estrogen treatment increases bone mass and reduces fat mass but is associated with adverse effects in postmenopausal women. Knowledge regarding tissue-specific estrogen signaling is important to aid the development of new tissue-specific treatments. We hypothesized that the posttranslational modification phosphorylation in estrogen receptor alpha (ERα) may modulate ERα activity in a tissue-dependent manner. Phosphorylation of site S122 in ERα has been shown in vitro to affect ERα activity, but the tissue-specific role in vivo is unknown. We herein developed and phenotyped a novel mouse model with a point mutation at the phosphorylation site 122 in ERα (S122A). Female S122A mice had increased fat mass and serum insulin levels but unchanged serum sex steroid levels, uterus weight, bone mass, thymus weight, and lymphocyte maturation compared to WT mice. In conclusion, phosphorylation site S122 in ERα has a tissue-dependent role with an impact specifically on fat mass in female mice. This study is the first to demonstrate in vivo that a phosphorylation site in a transactivation domain in a nuclear steroid receptor modulates the receptor activity in a tissue-dependent manner.

12.
Artigo em Inglês | MEDLINE | ID: mdl-33059368

RESUMO

CONTEXT: Serum testosterone concentrations decline with age, while serum sex hormone-binding globulin (SHBG) concentrations increase. OBJECTIVE: To analyse associations of baseline serum testosterone and SHBG concentrations, and calculated free testosterone (cFT) values, with all-cause and cause-specific mortality in men. DESIGN, SETTING AND PARTICIPANTS: The UK Biobank prospective cohort study of community-dwelling men 40-69 years-old, followed for 11 years. MAIN OUTCOME MEASURES: All-cause, atherosclerotic cardiovascular disease (CVD) and cancer-related mortality. Cox proportional hazards regression was performed, adjusting for age, waist circumference, medical conditions and other covariates. Models for testosterone included SHBG, and vice versa. RESULTS: In complete case analysis of 149,436 men with 10,053 deaths (1,925 CVD and 4,927 cancer-related), men with lower testosterone had higher mortality from any cause (lowest vs highest quintile, Q1 vs Q5, fully-adjusted hazard ratio [HR]=1.14, 95% confidence interval [CI]=1.06-1.22, overall trend P<0.001), and cancer (HR=1.20, CI=1.09-1.33, P<0.001), with no association for CVD deaths. Similar results were seen for cFT. Men with lower SHBG had lower mortality from any cause (Q1 vs Q5, HR=0.68, CI=0.63-0.73, P<0.001), CVD (HR=0.70, CI=0.59-0.83, P<0.001), and cancer (HR=0.80, CI=0.72-0.89, P<0.001). A multiply-imputed dataset (N=208,425, 15,914 deaths, 3,128 CVD and 7,468 cancer-related) and analysis excluding deaths within first two years (9,261, 1,734 and 4,534 events) yielded similar results. CONCLUSIONS: Lower serum testosterone is independently associated with higher all-cause and cancer-related, but not CVD-related, mortality in middle-aged to older men. Lower SHBG is independently associated with lower all-cause, CVD-related and cancer-related mortality. Confirmation and determination of causality requires mechanistic studies and prospective trials.

13.
Sci Rep ; 10(1): 18334, 2020 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-33110090

RESUMO

Sex steroids, such as estrogens and androgens, are important regulators of the humoral immune response. Studies in female mice have demonstrated that alteration of circulating estrogen concentration regulates antibody-mediated immunity. As males have normally little endogenous estrogen, we hypothesized that in males high estrogens and low androgens affect the immune system and enhance the allergic inflammatory response. Here, we studied transgenic male mice expressing human aromatase (AROM+). These animals have a high circulating estrogen to androgen ratio (E/A), causing female traits such as gynecomastia. We found that AROM+ male mice had significantly higher plasma immunoglobulin levels, particularly IgE. Flow cytometry analyses of splenocytes revealed changes in mature/immature B cell ratio together with a transcriptional upregulation of the Igh locus. Furthermore, higher proliferation rate and increased IgE synthesis after IgE class-switching was found. Subsequently, we utilized an ovalbumin airway challenge model to test the allergic response in AROM+ male mice. In line with above observations, an increase in IgE levels was measured, albeit no impact on immune cell infiltration into the lungs was detected. Together, our findings suggest that high circulating E/A in males significantly alters B cell function without any significant enhancement in allergic inflammation.

14.
FASEB J ; 34(11): 14440-14457, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32892421

RESUMO

Nerve growth factor (NGF) is critical for the development and maintenance of the peripheral sympathetic neurons. NGF is also involved in the ovarian sympathetic innervation and in the development and maintenance of folliculogenesis. Women with the endocrine disorder, polycystic ovary syndrome (PCOS), have an increased sympathetic nerve activity and increased ovarian NGF levels. The role of ovarian NGF excess in the PCOS pathophysiology and in the PCOS-related features is unclear. Here, using transgenic mice overexpressesing NGF in the ovarian theca cells (17NF mice), we assessed the female embryonic development, and the reproductive and metabolic profile in adult females. Ovarian NGF excess caused growth restriction in the female fetuses, and a delayed gonocyte and primary oocyte maturation. In adulthood, the 17NF mice displayed irregular estrous cycles and altered ovarian expression of steroidogenic and epigenetic markers. They also exhibited an increased sympathetic output with increased circulating dopamine, and metabolic dysfunction reflected by aberrant adipose tissue morphology and function, impaired glucose metabolism, decreased energy expenditure, and hepatic steatosis. These findings indicate that ovarian NGF excess leads to adverse fetal development and to reproductive and metabolic complications in adulthood, mirroring common features of PCOS. This work provides evidence that NGF excess may be implicated in the PCOS pathophysiology.

15.
Artigo em Inglês | MEDLINE | ID: mdl-32979890

RESUMO

OBJECTIVE: Serum testosterone concentrations are affected by factors unrelated to hypothalamo-pituitary-testicular axis pathology. We evaluated the impact of sociodemographic, lifestyle and medical factors, on serum testosterone and sex hormone-binding globulin (SHBG) in men aged 40-69 years. DESIGN: Cross-sectional analysis of 208,677 community-dwelling men from the UK Biobank. MEASUREMENTS: We analysed associations of different factors with serum testosterone and SHBG (immunoassays) and calculated free testosterone (cFT), using smoothed centile plots, linear mixed models and effect size estimates. RESULTS: Median (interquartile range) for serum testosterone was 11.6 (9.4-14.1) nmol/L, SHBG 36.9 (27.9-48.1) nmol/L and cFT 213 (178-255) pmol/L. Age and BMI were inversely associated with testosterone and cFT, while SHBG was associated with age and inversely with BMI (all P < .001). Living with a partner, (South) Asian ethnicity, never or previous smoker and some medical conditions were associated with lower testosterone. Poultry or fish eater, and higher physical activity were associated with higher testosterone (all P < .001). Testosterone was lowered by ~0.5 nmol/L across ages, ~1.5 nmol/L for BMI 30 vs 25 kg/m2 , ~2 nmol/L for (South) Asian ethnicity, living with partner, college/university qualifications, low red meat eater, insufficient physical activity and 0.3-1.0 nmol/L with cardiovascular disease or diabetes. Different combinations of these factors varied serum testosterone by ~4 nmol/L, SHBG by ~30 nmol/L and cFT by ~60 pmol/L. CONCLUSIONS: The identified modifiable risk factors support lifestyle-based interventions in men with low testosterone concentrations. Considering sociodemographic, lifestyle and medical factors facilitates more personalized interpretation of testosterone testing results with respect to existing reference ranges.

16.
Proc Natl Acad Sci U S A ; 117(40): 24986-24997, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-32958661

RESUMO

It has proven difficult to identify the underlying genes in complex autoimmune diseases. Here, we use forward genetics to identify polymorphisms in the vitamin D receptor gene (Vdr) promoter, controlling Vdr expression and T cell activation. We isolated these polymorphisms in a congenic mouse line, allowing us to study the immunomodulatory properties of VDR in a physiological context. Congenic mice overexpressed VDR selectively in T cells, and thus did not suffer from calcemic effects. VDR overexpression resulted in an enhanced antigen-specific T cell response and more severe autoimmune phenotypes. In contrast, vitamin D3-deficiency inhibited T cell responses and protected mice from developing autoimmune arthritis. Our observations are likely translatable to humans, as Vdr is overexpressed in rheumatic joints. Genetic control of VDR availability codetermines the proinflammatory behavior of T cells, suggesting that increased presence of VDR at the site of inflammation might limit the antiinflammatory properties of its ligand.


Assuntos
Inflamação/genética , Receptores de Calcitriol/genética , Linfócitos T/imunologia , Animais , Regulação da Expressão Gênica/genética , Humanos , Inflamação/imunologia , Camundongos , Polimorfismo Genético , Linfócitos T/metabolismo , Vitamina D/genética , Deficiência de Vitamina D/genética , Deficiência de Vitamina D/imunologia
17.
J Endocrinol ; 247(1): 69-85, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32755996

RESUMO

Gonadal steroids strongly contribute to the metabolic programming that shapes the susceptibility to the manifestation of diseases later in life, and the effect is often sexually dimorphic. Microbiome signatures, together with metabolic traits and sex steroid levels, were analyzed at adulthood in neonatally androgenized female rats, and compared with those of control male and female rats. Exposure of female rats to high doses of androgens on early postnatal life resulted in persistent alterations of the sex steroid profile later on life, namely lower progesterone and higher estradiol and estrone levels, with no effect on endogenous androgens. Neonatally androgenized females were heavier (10% at early adulthood and 26% at adulthood) than controls and had impaired glucose homeostasis observed by higher AUC of glucose in GTT and ITT when subjected to obesogenic manipulations. Androgenized female displayed overt alterations in gut microbiota, indicated especially by higher Bacteroidetes and lower Firmicutes abundance at early adulthood, which disappeared when animals were concurrently overfed at adulthood. Notably, these changes in gut microbiota were related with the intestinal expression of several miRNAs, such as miR-27a-3p, miR-29a-5p, and miR-100-3p. Our results suggest that nutritional and hormonal disruption at early developmental periods not only alters the metabolic programming of the individual later in life but also perturbs the architecture of gut microbiota, which may interact with the host by a cross-talk mediated by intestinal miRNAs; phenomena that may contribute to amplify the metabolic derangement caused by obesity, as seen in neonatally androgenized female rats.

18.
Hum Mol Genet ; 29(17): 2813-2830, 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-32716031

RESUMO

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders leading to infertility in women affecting reproductive, endocrine and metabolic systems. Recent genomewide association studies on PCOS cohorts revealed a single nucleotide polymorphism (SNP) in the ERBB4 receptor tyrosine kinase 4 gene, but its role in ovary development or during folliculogenesis remains poorly understood. Since no genetic animal models mimicking all PCOS reproductive features are available, we conditionally deleted Erbb4 in murine granulosa cells (GCs) under the control of Amh promoter. While we have demonstrated that Erbb4 deletion displayed aberrant ovarian function by affecting the reproductive function (asynchronous oestrous cycle leading to few ovulations and subfertility) and metabolic function (obesity), their ovaries also present severe structural and functional abnormalities (impaired oocyte development). Hormone analysis revealed an up-regulation of serum luteinizing hormone, hyperandrogenism, increased production of ovarian and circulating anti-Müllerian hormone. Our data implicate that Erbb4 deletion in GCs leads to defective intercellular junctions between the GCs and oocytes, causing changes in the expression of genes regulating the local microenvironment of the follicles. In vitro culture assays reducing the level of Erbb4 via shRNAs confirm that Erbb4 is essential for regulating Amh level. In conclusion, our results indicate a functional role for Erbb4 in the ovary, especially during folliculogenesis and its reduced expression plays an important role in reproductive pathophysiology, such as PCOS development.

19.
J Am Geriatr Soc ; 68(7): 1429-1437, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32633824

RESUMO

OBJECTIVES: Analyses performed by the Sarcopenia Definitions and Outcomes Consortium (SDOC) identified cut-points in several metrics of grip strength for consideration in a definition of sarcopenia. We describe the associations between the SDOC-identified metrics of low grip strength (absolute or standardized to body size/composition); low dual-energy x-ray absorptiometry (DXA) lean mass as previously defined in the literature (appendicular lean mass [ALM]/ht2 ); and slowness (walking speed <.8 m/s) with subsequent adverse outcomes (falls, hip fractures, mobility limitation, and mortality). DESIGN: Individual-level, sex-stratified pooled analysis. We calculated odds ratios (ORs) or hazard ratios (HRs) for incident falls, mobility limitation, hip fractures, and mortality. Follow-up time ranged from 1 year for falls to 8.8 ± 2.3 years for mortality. SETTING: Eight prospective observational cohort studies. PARTICIPANTS: A total of 13,421 community-dwelling men and 4,828 community-dwelling women. MEASUREMENTS Grip strength by hand dynamometry, gait speed, and lean mass by DXA. RESULTS: Low grip strength (absolute or standardized to body size/composition) was associated with incident outcomes, usually independently of slowness, in both men and women. ORs and HRs generally ranged from 1.2 to 3.0 for those below vs above the cut-point. DXA lean mass was not consistently associated with these outcomes. When considered together, those who had both muscle weakness by absolute grip strength (<35.5 kg in men and <20 kg in women) and slowness were consistently more likely to have a fall, hip fracture, mobility limitation, or die than those without either slowness or muscle weakness. CONCLUSION: Older men and women with both muscle weakness and slowness have a higher likelihood of adverse health outcomes. These results support the inclusion of grip strength and walking speed as components in a summary definition of sarcopenia. J Am Geriatr Soc 68:1429-1437, 2020.

20.
J Am Geriatr Soc ; 68(7): 1419-1428, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32633834

RESUMO

BACKGROUND: The Sarcopenia Definitions and Outcomes Consortium (SDOC) sought to identify cut points for muscle strength and body composition measures derived from dual-energy x-ray absorptiometry (DXA) that discriminate older adults with slow walking speed. This article presents the core analyses used to guide the SDOC position statements. DESIGN: Cross-sectional data analyses of pooled data. SETTING: University-based research assessment centers. PARTICIPANTS: Community-dwelling men (n = 13,652) and women: (n = 5,115) with information on lean mass by DXA, grip strength (GR), and walking speed. MEASUREMENTS: Thirty-five candidate sarcopenia variables were entered into sex-stratified classification and regression tree (CART) models to agnostically choose variables and cut points that discriminate slow walkers (<0.80 m/s). Models with alternative walking speed outcomes were also evaluated (<0.60 and <1.0 m/s and walking speed treated continuously). RESULTS: CART models identified GR/body mass index (GRBMI) and GR/total body fat (GRTBF) as the primary discriminating variables for slowness in men and women, respectively. Men with GRBMI of 1.05 kg/kg/m2 or less were approximately four times more likely to be slow walkers than those with GRBMI of greater than 1.05 kg/kg/m2 . Women with GRTBF of less than 0.65 kg/kg were twice as likely to be slow walkers than women with GRTBF of 0.65 kg/kg or greater. Models with alternative walking speed outcomes selected only functions of GR as primary discriminators of slowness in both men and women. DXA-derived lean mass measures did not consistently discriminate slow walkers. CONCLUSION: GR with and without adjustments for body size and composition consistently discriminated older adults with slowness. CART models did not select DXA-based lean mass as a primary discriminator of slowness. These results were presented to an SDOC Consensus Panel, who used them and other information to develop the SDOC Position Statements. J Am Geriatr Soc 68:1419-1428, 2020.

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