RESUMO
Triglyceride (TG)-lowering LPL variants in combination with genetic LDL-C-lowering variants are associated with reduced risk of coronary artery disease (CAD). Genetic variation in the APOA5 gene encoding apolipoprotein A-V also strongly affects TG levels, but the potential clinical impact and underlying mechanisms are yet to be resolved. Here, we aimed to study the effects of APOA5 genetic variation on CAD risk and plasma lipoproteins through factorial genetic association analyses. Using data from 309,780 European-ancestry participants from the UK Biobank, we evaluated the effects of lower TG levels as a result of genetic variation in APOA5 and/or LPL on CAD risk with or without a background of reduced LDL-C. Next, we compared lower TG levels via APOA5 and LPL variation with over 100 lipoprotein measurements in a combined sample from the Netherlands Epidemiology of Obesity study (N = 4,838) and the Oxford Biobank (N = 6,999). We found that lower TG levels due to combined APOA5 and LPL variation and genetically-influenced lower LDL-C levels afforded the largest reduction in CAD risk (odds ratio: 0.78 (0.73-0.82)). Compared to patients with genetically-influenced lower TG via LPL, genetically-influenced lower TG via APOA5 had similar and independent, but notably larger, effects on the lipoprotein profile. Our results suggest that lower TG levels as a result of APOA5 variation have strong beneficial effects on CAD risk and the lipoprotein profile, which suggest apo A-V may be a potential novel therapeutic target for CAD prevention.
Assuntos
Apolipoproteína A-V/metabolismo , Doença da Artéria Coronariana , Apolipoproteína A-V/genética , Apolipoproteínas A/genética , LDL-Colesterol , Doença da Artéria Coronariana/genética , Humanos , Lipoproteínas , TriglicerídeosRESUMO
BACKGROUND: Observational studies suggest interconnections between thyroid status, metabolism, and risk of coronary artery disease (CAD), but causality remains to be proven. The present study aimed to investigate the potential causal relationship between thyroid status and cardiovascular disease and to characterize the metabolomic profile associated with thyroid status. METHODS: Multi-cohort two-sample Mendelian randomization (MR) was performed utilizing genome-wide significant variants as instruments for standardized thyrotropin (TSH) and free thyroxine (fT4) within the reference range. Associations between TSH and fT4 and metabolic profile were investigated in a two-stage manner: associations between TSH and fT4 and the full panel of 161 metabolomic markers were first assessed hypothesis-free, then directional consistency was assessed through Mendelian randomization, another metabolic profile platform, and in individuals with biochemically defined thyroid dysfunction. RESULTS: Circulating TSH was associated with 52/161 metabolomic markers, and fT4 levels were associated with 21/161 metabolomic markers among 9432 euthyroid individuals (median age varied from 23.0 to 75.4 years, 54.5% women). Positive associations between circulating TSH levels and concentrations of very low-density lipoprotein subclasses and components, triglycerides, and triglyceride content of lipoproteins were directionally consistent across the multivariable regression, MR, metabolomic platforms, and for individuals with hypo- and hyperthyroidism. Associations with fT4 levels inversely reflected those observed with TSH. Among 91,810 CAD cases and 656,091 controls of European ancestry, per 1-SD increase of genetically determined TSH concentration risk of CAD increased slightly, but not significantly, with an OR of 1.03 (95% CI 0.99-1.07; p value 0.16), whereas higher genetically determined fT4 levels were not associated with CAD risk (OR 1.00 per SD increase of fT4; 95% CI 0.96-1.04; p value 0.59). CONCLUSIONS: Lower thyroid status leads to an unfavorable lipid profile and a somewhat increased cardiovascular disease risk.
Assuntos
Doenças Cardiovasculares , Tireotropina , Adulto , Idoso , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , Feminino , Humanos , Lipídeos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Tiroxina , Adulto JovemRESUMO
BACKGROUND: Sleep traits are associated with cardiometabolic disease risk, with evidence from Mendelian randomization (MR) suggesting that insomnia symptoms and shorter sleep duration increase coronary artery disease risk. We combined adjusted multivariable regression (AMV) and MR analyses of phenotypes of unfavourable sleep on 113 metabolomic traits to investigate possible biochemical mechanisms linking sleep to cardiovascular disease. METHODS: We used AMV (N = 17,368) combined with two-sample MR (N = 38,618) to examine effects of self-reported insomnia symptoms, total habitual sleep duration, and chronotype on 113 metabolomic traits. The AMV analyses were conducted on data from 10 cohorts of mostly Europeans, adjusted for age, sex, and body mass index. For the MR analyses, we used summary results from published European-ancestry genome-wide association studies of self-reported sleep traits and of nuclear magnetic resonance (NMR) serum metabolites. We used the inverse-variance weighted (IVW) method and complemented this with sensitivity analyses to assess MR assumptions. RESULTS: We found consistent evidence from AMV and MR analyses for associations of usual vs. sometimes/rare/never insomnia symptoms with lower citrate (- 0.08 standard deviation (SD)[95% confidence interval (CI) - 0.12, - 0.03] in AMV and - 0.03SD [- 0.07, - 0.003] in MR), higher glycoprotein acetyls (0.08SD [95% CI 0.03, 0.12] in AMV and 0.06SD [0.03, 0.10) in MR]), lower total very large HDL particles (- 0.04SD [- 0.08, 0.00] in AMV and - 0.05SD [- 0.09, - 0.02] in MR), and lower phospholipids in very large HDL particles (- 0.04SD [- 0.08, 0.002] in AMV and - 0.05SD [- 0.08, - 0.02] in MR). Longer total sleep duration associated with higher creatinine concentrations using both methods (0.02SD per 1 h [0.01, 0.03] in AMV and 0.15SD [0.02, 0.29] in MR) and with isoleucine in MR analyses (0.22SD [0.08, 0.35]). No consistent evidence was observed for effects of chronotype on metabolomic measures. CONCLUSIONS: Whilst our results suggested that unfavourable sleep traits may not cause widespread metabolic disruption, some notable effects were observed. The evidence for possible effects of insomnia symptoms on glycoprotein acetyls and citrate and longer total sleep duration on creatinine and isoleucine might explain some of the effects, found in MR analyses of these sleep traits on coronary heart disease, which warrant further investigation.
Assuntos
Doença da Artéria Coronariana , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Doenças Metabólicas , Sono , Idoso , Doença da Artéria Coronariana/epidemiologia , Creatinina/metabolismo , Estudos Transversais , Humanos , Isoleucina/metabolismo , Doenças Metabólicas/complicações , Doenças Metabólicas/epidemiologia , Fenótipo , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
BACKGROUND AND AIMS: Outdoor temperature and bright sunlight may directly and/or indirectly modulate systemic metabolism. We assessed the associations between outdoor temperature and bright sunlight duration with metabolomics. METHODS AND RESULTS: Cross-sectional analyses were undertaken in non-diabetic individuals from the Oxford BioBank (OBB; N = 6368; mean age 47.0 years, males 44%) and the Netherlands Epidemiology of Obesity (NEO; N = 5916; mean age 55.6 years, males 43%) study. Data on mean outdoor bright sunlight and temperature were collected from local weather stations in the week prior to blood sampling. Fasting serum levels of 148 metabolites, including 14 lipoprotein subclasses, were measured using NMR spectroscopy. Linear regression analyses were performed to assess the associations between mean outdoor temperature and bright sunlight duration with metabolomics adjusted for age, sex, body mass index, season and either outdoor temperature or bright sunlight. A higher mean outdoor temperature was associated with increased serum concentrations of lipoprotein (sub)particles (ß (SE) = 0.064 (0.018) SD per 5 °C, p = 5.03e-4) and certain amino acids such as phenylalanine (0.066 (0.016) SD, p = 6.44e-05) and leucine (0.111 (0.018) SD, p = 1.25e-09). In contrast, longer duration of bright sunlight was specifically associated with lower concentrations of very low-density lipoprotein (sub)particles (e.g., VLDL cholesterol (-0.024 (0.005) SD per 1-h bright sunlight, p = 8.06e-6)). The direction of effects was generally consistent between the OBB and NEO, although effect sizes were generally larger in the OBB. CONCLUSIONS: Increased bright sunlight duration is associated with an improved metabolic profile whilst higher outdoor temperature may adversely impact cardiometabolic health.
Assuntos
Aminoácidos/sangue , Metabolismo Energético , Lipídeos/sangue , Luz Solar , Temperatura , Adulto , Idoso , Biomarcadores/sangue , Estudos Transversais , Inglaterra , Feminino , Nível de Saúde , Humanos , Masculino , Metabolômica , Pessoa de Meia-Idade , Países Baixos , Estudos Prospectivos , Fatores de TempoRESUMO
AIMS/HYPOTHESIS: Circulating succinate and 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) were recently shown to promote brown adipocyte thermogenesis and protect against metabolic disorders in rodents. This study aimed to evaluate the associations between plasma levels of these metabolites and adiposity and metabolic profile in humans. METHODS: Fasting plasma succinate and 12,13-diHOME levels were quantified using ultra HPLC-tandem MS in 2248 individuals (50% female, mean age 41.3 ± 5.9 years, mean BMI 26.1 ± 4.6 kg/m2) in addition to fasting plasma biochemistry. Total and regional adiposity were assessed with dual-energy x-ray absorptiometry. An age- and sex-adjusted linear regression model was used to determine the associations between succinate and 12,13-diHOME levels and body composition and metabolic profile. Two-sample Mendelian randomisation was used to assess the associations between genetically determined BMI and metabolic traits with circulating plasma succinate and 12,13-diHOME. RESULTS: A one-SD higher plasma succinate and 12,13-diHOME concentration was associated with a 0.15 SD (95% CI 0.28, 0.03) and 0.08 SD (0.15, 0.01) lower total fat mass respectively. Additionally, a one-SD higher plasma 12,13-diHOME level was associated with a 0.09 SD (0.16, 0.02) lower fasting plasma insulin and 0.10 SD (0.17, 0.04) lower plasma triacylglycerol. In Mendelian randomisation analyses, genetically determined higher BMI, fasting hyperinsulinaemia and elevated lipid levels were not associated with changes in either plasma succinate or plasma 12,13-diHOME concentrations. No indications of bias due to directional pleiotropy were detected in the Mendelian randomisation analyses. CONCLUSIONS/INTERPRETATION: Our findings tentatively suggest that plasma succinate and 12,13-diHOME may play a role in the regulation of energy metabolism and brown adipose tissue activation in humans. Further studies encompassing direct assessment of brown adipose tissue activity and dietary supplementation are necessary to investigate the potential beneficial effects of these metabolites on systemic metabolism.
Assuntos
Adiposidade , Ácidos Oleicos/metabolismo , Ácido Succínico/química , Termogênese , Adipócitos/metabolismo , Tecido Adiposo Marrom/metabolismo , Adulto , Índice de Massa Corporal , Estudos Transversais , Metabolismo Energético , Feminino , Humanos , Resistência à Insulina , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , ObesidadeRESUMO
OBJECTIVE: Non-functioning pituitary adenomas (NFA) may be associated with significant morbidity. Published data on the quality of life (QoL) of patients with NFA are scarce and conflicting. In view of the discordant findings and the advances in the management of these subjects, we aimed to evaluate the QoL in patients with NFA followed up in a tertiary endocrine UK referral centre. SUBJECTS AND METHODS: All consecutive patients with NFA attending the outpatient clinic in the Department of Endocrinology in Oxford over a 6-month period (n = 193) were offered 3 health-related QoL questionnaires [Short Form 36 (SF36), Nottingham Health Profile (NHP), European Quality of Life Scale (EuroQoL)] to complete. Patient outcomes (response rate 93.3%) were compared with age-related UK reference values. RESULTS: None of the QoL scores in the SF-36 or the 5 dimensions of health in the EuroQoL was different from the reference values. The visual analogue scale (VAS) score (EuroQoL) was slightly compromised (P = 0.041). In the NHP questionnaire, males had no parameter significantly affected, whereas females performed worse in 1/6 areas (energy levels). Tumour recurrence was an independent predictor for compromised VAS score and for anxiety/depression (EuroQoL), and visual field defects for more frequent problems with interests/hobbies (NHP). CONCLUSIONS: Overall, the health-related QoL and perception of subjective health in patients with NFA was not compromised to any major extent suggesting that we can now offer the prospect of treatment and replacement, which will provide a normal or near-normal QoL. Specific groups are affected in various dimensions, necessitating measures to compensate for predisposing factors.
Assuntos
Neoplasias Hipofisárias/metabolismo , Qualidade de Vida , Hormônio Adrenocorticotrópico/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tireotropina/metabolismoRESUMO
OBJECTIVE: Observational studies have reported bidirectional associations between metabolic syndrome (MetS) traits and short leukocyte telomere length (LTL), a TL marker in somatic tissues and a proposed risk factor for age-related degenerative diseases. However, in Mendelian randomization studies, longer LTL has been paradoxically associated with higher MetS risk. This study investigated the hypothesis that shorter LTL might be a consequence of metabolic dysfunction. METHODS: This study undertook univariable and multivariable Mendelian randomization. As instrumental variables for MetS traits, all of the genome-wide significant independent signals identified in genome-wide association studies for anthropometric, glycemic, lipid, and blood pressure traits conducted in European individuals were used. Summary-level data for LTL were obtained from a genome-wide association study conducted in the UK Biobank. RESULTS: Higher BMI was associated with shorter LTL (ß = -0.039, 95% CI: -0.058 to -0.020, p = 5 × 10-5 ) equivalent to 1.70 years of age-related LTL change. In contrast, higher low-density lipoprotein cholesterol was associated with longer LTL (ß = 0.022, 95% CI: 0.007 to 0.037, p = 0.003) equivalent to 0.96 years of age-related LTL change. Mechanistically, increased low-grade systemic inflammation, as measured by circulating C-reactive protein, and lower circulating linoleic acid levels might link higher BMI to shorter LTL. CONCLUSIONS: Overweight and obesity might promote the development of aging-related degenerative diseases by accelerating telomere shortening.
Assuntos
Síndrome Metabólica , Humanos , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Envelhecimento , Telômero/genética , Leucócitos/metabolismoRESUMO
Obesity and upper-body fat distribution are independent, cardiometabolic risk factors but whether they also display comparable associations with cancer risk is unknown. We investigated the causal relationships between body mass index (BMI) and BMI-adjusted waist-to-hip ratio (WHRadjBMI) and cancer risk and searched for potential drivers linking these traits to carcinogenesis using two-sample and multivariable Mendelian randomisation. In women, genetically instrumented higher BMI was associated with lower breast (OR = 0.87, 95% CI 0.81-0.93) and higher endometrial (OR = 1.75, 95% CI 1.55-1.96) cancer risk whilst WHRadjBMI was associated with higher colon cancer risk (OR = 1.22, 95% CI 1.07-1.42). In men, elevated BMI was associated with lower prostate cancer risk (OR = 0.91, 95% CI 0.85-0.98). Mechanistically, testosterone and insulin mediated 21% and 35%, respectively of the total, genetically determined association of BMI with endometrial cancer risk whilst HDL cholesterol and IGF-1 mediated 40% and 22%, respectively of the association between BMI and breast cancer risk. In men, testosterone mediated 21% of the association between BMI and prostate cancer risk. Colon cancer aside, the total amount of body fat might be more important than its location in modulating cancer susceptibility due to differential effects of obesity and fat distribution on adiposity-associated cancer drivers.
Assuntos
Neoplasias da Mama , Neoplasias do Colo , Neoplasias da Próstata , Masculino , Humanos , Feminino , Fatores de Risco , Obesidade/complicações , Obesidade/epidemiologia , Obesidade/genética , Adiposidade/genética , Neoplasias da Mama/etiologia , Neoplasias da Mama/genética , Tecido Adiposo , Índice de Massa Corporal , Neoplasias da Próstata/etiologia , Neoplasias da Próstata/genética , Neoplasias do Colo/etiologia , Neoplasias do Colo/genética , TestosteronaRESUMO
OBJECTIVE: Epidemiological and clinical studies have highlighted important roles for sex hormones in the regulation of fat distribution and systemic metabolism. We investigated the bidirectional associations between bioavailable serum testosterone (BioT) in both sexes and oestradiol (E2) in men and adiposity and metabolic traits using Mendelian randomisation (MR). DESIGN AND METHODS: As genetic instruments for sex hormones, we selected all the genome-wide significant, independent signals from a genome-wide association studies (GWAS) in up to 425 097 European ancestry UK Biobank participants. European population-specific, summary-level data for adiposity, metabolic, and blood pressure traits were obtained from the largest publicly available GWAS. Sex-specific, two-sample MR analyses were used to estimate the associations of sex hormones with these traits and vice versa. RESULTS: In women, higher BioT was associated with obesity, upper-body fat distribution, and low HDL-cholesterol although, based on analyses modelling the sex hormone-binding globulin-independent effects of BioT, the last two associations might be indirect. Conversely, obesity and android fat distribution were associated with elevated serum BioT. In men, higher BioT was associated with lower hip circumference and lower fasting glucose. Reciprocally, obesity was associated with lower BioT and higher E2, while upper-body fat distribution and raised triglycerides were associated with lower E2. CONCLUSIONS: Adipose tissue and metabolic dysfunction are associated with deranged sex hormone levels in both sexes. In women, elevated BioT might be a cause of obesity. Conversely, in men, higher BioT appears to have beneficial effects on adiposity and glucose metabolism.
Assuntos
Adiposidade/genética , Hormônios Esteroides Gonadais/genética , Feminino , Humanos , Masculino , Análise da Randomização MendelianaRESUMO
BACKGROUND: Body composition is associated with bone mineral density (BMD), but the precise associations between body fat distribution and BMD remain unclear. The regional adipose tissue depots have different metabolic profiles. We hypothesized that they would have independent associations with BMD. RESEARCH DESIGN AND METHODS: We used data from 4,900 healthy individuals aged 30-50 years old from the Oxford Biobank to analyze associations between regional fat mass, lean mass and total BMD. RESULTS: Total lean mass was strongly positively associated with BMD. An increase in total BMD was observed with increasing mass of all the fat depots, as measured either by anthropometry or DXA, when accounting for lean mass. However, on adjustment for both total fat mass and lean mass, fat depot specific associations emerged. Increased android and visceral adipose tissue mass in men, and increased visceral adipose tissue mass in women, were associated with lower BMD. CONCLUSIONS: Fat distribution alters the association between adiposity and BMD.
Assuntos
Bancos de Espécimes Biológicos , Densidade Óssea , Absorciometria de Fóton , Adulto , Distribuição da Gordura Corporal , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: Non-coding genetic variation at TCF7L2 is the strongest genetic determinant of type 2 diabetes (T2D) risk in humans. TCF7L2 encodes a transcription factor mediating the nuclear effects of WNT signaling in adipose tissue (AT). In vivo studies in transgenic mice have highlighted important roles for TCF7L2 in adipose tissue biology and systemic metabolism. OBJECTIVE: To map the expression of TCF7L2 in human AT, examine its role in human adipose cell biology in vitro, and investigate the effects of the fine-mapped T2D-risk allele at rs7903146 on AT morphology and TCF7L2 expression. METHODS: Ex vivo gene expression studies of TCF7L2 in whole and fractionated human AT. In vitro TCF7L2 gain- and/or loss-of-function studies in primary and immortalized human adipose progenitor cells (APCs) and mature adipocytes (mADs). AT phenotyping of rs7903146 T2D-risk variant carriers and matched controls. RESULTS: Adipose progenitors (APs) exhibited the highest TCF7L2 mRNA abundance compared to mature adipocytes and adipose-derived endothelial cells. Obesity was associated with reduced TCF7L2 transcript levels in whole subcutaneous abdominal AT but paradoxically increased expression in APs. In functional studies, TCF7L2 knockdown (KD) in abdominal APs led to dose-dependent activation of WNT/ß-catenin signaling, impaired proliferation and dose-dependent effects on adipogenesis. Whilst partial KD enhanced adipocyte differentiation, near-total KD impaired lipid accumulation and adipogenic gene expression. Over-expression of TCF7L2 accelerated adipogenesis. In contrast, TCF7L2-KD in gluteal APs dose-dependently enhanced lipid accumulation. Transcriptome-wide profiling revealed that TCF7L2 might modulate multiple aspects of AP biology including extracellular matrix secretion, immune signaling and apoptosis. The T2D-risk allele at rs7903146 was associated with reduced AP TCF7L2 expression and enhanced AT insulin sensitivity. CONCLUSIONS: TCF7L2 plays a complex role in AP biology and has both dose- and depot-dependent effects on adipogenesis. In addition to regulating pancreatic insulin secretion, genetic variation at TCF7L2 might also influence T2D risk by modulating AP function.
Assuntos
Tecido Adiposo , Diabetes Mellitus Tipo 2 , Proteína 2 Semelhante ao Fator 7 de Transcrição , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Células Endoteliais/metabolismo , Predisposição Genética para Doença , Humanos , Metabolismo dos Lipídeos , Proteína 2 Semelhante ao Fator 7 de Transcrição/genética , Proteína 2 Semelhante ao Fator 7 de Transcrição/metabolismoRESUMO
Mechanisms governing regional human adipose tissue (AT) development remain undefined. Here, we show that the long non-coding RNA HOTAIR (HOX transcript antisense RNA) is exclusively expressed in gluteofemoral AT, where it is essential for adipocyte development. We find that HOTAIR interacts with polycomb repressive complex 2 (PRC2) and we identify core HOTAIR-PRC2 target genes involved in adipocyte lineage determination. Repression of target genes coincides with PRC2 promoter occupancy and H3K27 trimethylation. HOTAIR is also involved in modifying the gluteal adipocyte transcriptome through alternative splicing. Gluteal-specific expression of HOTAIR is maintained by defined regions of open chromatin across the HOTAIR promoter. HOTAIR expression levels can be modified by hormonal (estrogen, glucocorticoids) and genetic variation (rs1443512 is a HOTAIR eQTL associated with reduced gynoid fat mass). These data identify HOTAIR as a dynamic regulator of the gluteal adipocyte transcriptome and epigenome with functional importance for human regional AT development.
Assuntos
Complexo Repressor Polycomb 2 , RNA Longo não Codificante/genética , Cromatina , Estrogênios , Humanos , Complexo Repressor Polycomb 2/genética , Complexo Repressor Polycomb 2/metabolismo , Regiões Promotoras Genéticas/genética , RNA Longo não Codificante/metabolismo , Transcriptoma/genéticaRESUMO
Observational studies have revealed associations between short leucocyte telomere length (LTL), a TL marker in somatic tissues and multiple Metabolic Syndrome (MetS) traits. Animal studies have supported these findings by showing that increased telomere attrition leads to adipose tissue dysfunction and insulin resistance. We investigated the associations between genetically instrumented LTL and MetS traits using Mendelian Randomisation (MR). Fifty-two independent variants identified at FDR<0.05 from a genome-wide association study (GWAS) including 78,592 Europeans and collectively accounting for 2.93% of LTL variance were selected as genetic instruments for LTL. Summary-level data for MetS traits and for the MetS as a binary phenotype were obtained from the largest publicly available GWAS and two-sample MR analyses were used to estimate the associations of LTL with these traits. The combined effect of the genetic instruments was modelled using inverse variance weighted regression and sensitivity analyses with MR-Egger, weighted-median and MR-PRESSO were performed to test for and correct horizonal pleiotropy. Genetically instrumented longer LTL was associated with higher waist-to-hip ratio adjusted for body mass index (ß = 0.045 SD, SE = 0.018, p = 0.01), raised systolic (ß = 1.529 mmHg, SE = 0.332, p = 4x10-6 ) and diastolic (ß = 0.633 mmHg, SE = 0.222, p = 0.004) blood pressure, and increased MetS risk (OR = 1.133, 95% CI 1.057-1.215). Consistent results were obtained in sensitivity analyses, which provided no evidence of unbalanced horizontal pleiotropy. Telomere shortening might not be a major driver of cellular senescence and dysfunction in human adipose tissue. Future experimental studies should examine the mechanistic bases for the links between longer LTL and increased upper-body fat distribution and raised blood pressure.
Assuntos
Análise da Randomização Mendeliana/métodos , Síndrome Metabólica/genética , Telômero/genética , HumanosRESUMO
BACKGROUND: Cognitive impairment (CI) affects 35-65% of multiple sclerosis (MS) patients. The Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) has been proposed as a highly feasible and cost-effective tool for cognitive impairment (CI) screening in MS. The tool yields scores that should, ideally, readily convey patients' cognitive status to the clinicians. METHODS: To this aim, this study sought for cut-off scores of the three BICAMS test in a sample of 960 MS patients. We used three definitions for CI: 1.5, 1,65 and 2 standard deviations below the mean. Receiver operating characteristic (ROC) statistics helped us determine the capacity of BICAMS to diagnose CI. Optimal cut-offs were determined by the delta distance. Positive and negative predictive values, along with overall accuracy were also calculated. RESULTS: Symbol Digit Modalities Test (SDMT) and California Verbal Learning Test-II (CVLT-II) showed a diagnostic accuracy ranging from 74.6 to 77.4%, across the three CI definitions. The accuracy of Brief Visuospatial Memory Test-Revised (BVMT-R) was over 88%. SDMT had a balanced sensitivity, while CVLT-II and BVMT-R had higher specificities than sensitivities at detecting CI. More specifically, BVMT-R showed 100% specificity for all CI definitions. Raw cut-off scores for BICAMS tests are also provided within the manuscript, along with the diagnostic calculations. CONCLUSIONS: In this study, we confirmed that BICAMS is a good screening tool for CI and that simple cut-offs can be used in the everyday neurological practice.
Assuntos
Disfunção Cognitiva , Esclerose Múltipla , Cognição , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/etiologia , Humanos , Esclerose Múltipla/complicações , Esclerose Múltipla/diagnóstico , Testes Neuropsicológicos , Curva ROCRESUMO
BACKGROUND AND AIMS: Mendelian randomization studies have shown that triglyceride (TG)- lowering lipoprotein lipase (LPL) alleles and low-density lipoprotein-cholesterol (LDL-C)-lowering alleles have independent beneficial associations on cardiovascular disease (CVD) risk. We aimed to provide further insight into this observation by applying Mendelian randomization analyses of genetically-influenced TG and LDL-C levels on plasma metabolomic profiles. METHODS: We quantified over 100 lipoprotein metabolomic measures in the Netherlands Epidemiology of Obesity (NEO) study (N = 4838) and Oxford Biobank (OBB) (N = 6999) by nuclear magnetic resonance (NMR) spectroscopy. Weighted genetic scores for TG via five LPL alleles and LDL-C via 19 alleles were calculated and dichotomized by the median, resulting in four genotype combinations of high/low TG and high/low LDL-C. We performed linear regression analyses using a two × two design with the group with genetically-influenced high TG and LDL-C as a reference. RESULTS: Compared to the individual groups with genetically-influenced lower TG or lower LDL-C only, the group with combined genetically-influenced lower TG and LDL-C showed an overall independent and additive pattern of changes in metabolomic measures. Over 100 measures were different (p < 1.35 × 10-3) compared to the reference, with effect sizes and directionality being similar in NEO and OBB. Most notably, levels of all very-low density lipoprotein (VLDL) and LDL sub-particles were lower. CONCLUSIONS: Our findings provide evidence that TG-lowering on top of LDL-C-lowering has additive beneficial effects on the lipoprotein profile compared to TG-lowering or LDL-C-lowering only, which is in accordance with reported additive genetic effects on CVD risk reduction.
Assuntos
Lipase , Lipase Lipoproteica , Alelos , LDL-Colesterol/genética , Lipase Lipoproteica/genética , Lipoproteínas , Países Baixos , TriglicerídeosRESUMO
An inability of adipose tissue to expand consequent to exhausted capacity to recruit new adipocytes might underlie the association between obesity and insulin resistance. Adipocytes arise from mesenchymal precursors whose commitment and differentiation along the adipocytic lineage is tightly regulated. These regulatory factors mediate cross-talk between adipose cells, ensuring that adipocyte growth and differentiation are coupled to energy storage demands. The WNT family of autocrine and paracrine growth factors regulates adult tissue maintenance and remodelling and, consequently, is well suited to mediate adipose cell communication. Indeed, several recent reports, summarized in this review, implicate WNT signalling in regulating adipogenesis. Manipulating the WNT pathway to alter adipose cellular makeup, therefore, constitutes an attractive drug-development target to combat obesity-associated metabolic complications.
Assuntos
Adipogenia/genética , Proteínas Wnt/fisiologia , Adipogenia/fisiologia , Animais , Metabolismo Energético/genética , Metabolismo Energético/fisiologia , Humanos , Mediadores da Inflamação/fisiologia , Células-Tronco Mesenquimais/fisiologia , Modelos Biológicos , Obesidade/etiologia , Obesidade/genética , PPAR gama/fisiologia , Transdução de Sinais/genética , Proteínas Wnt/genética , beta Catenina/genética , beta Catenina/fisiologiaRESUMO
BACKGROUND: Data on the prevalence and type of endocrine disorders in ß-thalassemia intermedia (ß-TI) patients are scarce. This multicenter study was designed to determine the prevalence of endocrine complications and the associated risk factors in a large group of ß-TI patients. METHODS: In this cross-sectional multicenter study, 726 ß-TI patients, aged 2.5-80 years, registered at 12 thalassemic centers, from nine countries, were enrolled during 2017. In a subgroup of 522 patients (mean age 30.8 ± 12.1; range: 2.5-80 years) from Qatar, Iran, Oman, Cyprus, and Jordan detailed data were available. RESULTS: Overall, the most prevalent complications were osteopenia/osteoporosis (22.3%), hypogonadism (10.1%), and primary hypothyroidism (5.3%). In the subgroup multivariate analysis, older age was a risk factor for osteoporosis (Odds ratio: 7.870, 95% CI: 4.729-13.099, P < 0.001), hypogonadism (Odds ratio: 6.310, 95% CI: 2.944-13.521, P < 0.001), and non-insulin-dependent diabetes mellitus (NIDDM; Odds ratio: 17.67, 95% CI: 2.217-140.968, P = 0.007). Splenectomy was a risk factor for osteoporosis (Odds ratio: 1.736, 95% CI: 1.012-2.977, P = 0.045). Hydroxyurea was identified as a "protective factor" for NIDDM (Odds ratio: 0.259, 95% CI: 0.074-0.902, P = 0.034). CONCLUSIONS: To the best of our knowledge, this is the largest cohort of ß-TI patients with endocrine disorders evaluated in extremely heterogenic thalassemic populations for age, clinical, hematological, and molecular composition. The study demonstrates that endocrine complications are less common in patients with ß-TI compared with ß-TM patients. However, regular monitoring with timely diagnosis and proper management is crucial to prevent endocrine complications in ß-TI patients.
Assuntos
Diabetes Mellitus Tipo 2 , Doenças do Sistema Endócrino , Talassemia beta , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Estudos Transversais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Doenças do Sistema Endócrino/epidemiologia , Doenças do Sistema Endócrino/etiologia , Humanos , Irã (Geográfico) , Pessoa de Meia-Idade , Adulto Jovem , Talassemia beta/complicações , Talassemia beta/epidemiologiaRESUMO
Fat distribution is an independent cardiometabolic risk factor. However, its molecular and cellular underpinnings remain obscure. Here we demonstrate that two independent GWAS signals at RSPO3, which are associated with increased body mass index-adjusted waist-to-hip ratio, act to specifically increase RSPO3 expression in subcutaneous adipocytes. These variants are also associated with reduced lower-body fat, enlarged gluteal adipocytes and insulin resistance. Based on human cellular studies RSPO3 may limit gluteofemoral adipose tissue (AT) expansion by suppressing adipogenesis and increasing gluteal adipocyte susceptibility to apoptosis. RSPO3 may also promote upper-body fat distribution by stimulating abdominal adipose progenitor (AP) proliferation. The distinct biological responses elicited by RSPO3 in abdominal versus gluteal APs in vitro are associated with differential changes in WNT signalling. Zebrafish carrying a nonsense rspo3 mutation display altered fat distribution. Our study identifies RSPO3 as an important determinant of peripheral AT storage capacity.
Assuntos
Adipócitos/citologia , Adipócitos/metabolismo , Distribuição da Gordura Corporal , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Trombospondinas/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Adipócitos/efeitos dos fármacos , Tecido Adiposo/metabolismo , Adiposidade/genética , Adulto , Alelos , Animais , Biomarcadores/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Tamanho Celular/efeitos dos fármacos , Doxiciclina/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Pessoa de Meia-Idade , Mutação/genética , Polimorfismo de Nucleotídeo Único/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Caracteres Sexuais , Células-Tronco/metabolismo , Trombospondinas/genética , Relação Cintura-Quadril , Via de Sinalização Wnt/efeitos dos fármacos , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genéticaRESUMO
CONTEXT: Seasonal variation in cold and light exposure may influence metabolic health. OBJECTIVE: We assessed the associations of bright sunlight and outdoor temperature with measures of glucose and lipid metabolism in two populations of middle-aged European subjects. DESIGN: Cross-sectional study. SETTING: Two population-based European cohorts. PARTICIPANTS: Middle-aged nondiabetic subjects from the Oxford Biobank (OBB; N = 4327; mean age, 41.4 years) and the Netherlands Epidemiology of Obesity (NEO) study (N = 5899; mean age, 55.6 years). INTERVENTIONS: Data on outdoor bright sunlight and temperature collected from local weather stations. MAIN OUTCOME MEASURES: Insulin resistance and fasting lipid levels. Multivariable regression analyses were adjusted for age, sex, percentage body fat, season, and either outdoor temperature or bright sunlight. RESULTS: In the OBB cohort, increased bright sunlight exposure was associated with lower fasting insulin [-1.27% (95% CI, -2.09 to -0.47%) per extra hour of bright sunlight], lower homeostatic model assessment for insulin resistance (-1.36%; 95% CI, -2.23 to -0.50), lower homeostatic model assessment for ß-cell function (-0.80%; 95% CI, -1.31 to -0.30), and lower triglyceride (-1.28%; 95% CI, -2.07 to -0.50) levels. In the NEO cohort generally unidirectional but weaker associations were observed. No associations between outdoor temperature and measures of glucose or lipid metabolism were detected following adjustment for bright sunlight. CONCLUSIONS: Bright sunlight, but not outdoor temperature, might be associated with increased insulin sensitivity and lower triglyceride levels.
Assuntos
Resistência à Insulina , Luz Solar , Temperatura , Tecido Adiposo , Adulto , Glicemia/metabolismo , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Estudos Transversais , Inglaterra , Feminino , Humanos , Insulina/metabolismo , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Países Baixos , Sobrepeso/metabolismo , Estações do Ano , Triglicerídeos/metabolismo , Tempo (Meteorologia) , População BrancaRESUMO
Brown adipose tissue (BAT) is a potential target to treat cardiometabolic disorders because of its capacity to combust glucose and fatty acids for thermoregulation. Its cellular and molecular investigation in humans is hampered by the limited availability of cell material and the heterogeneity of BAT between and within individuals. In this study, monoclonal lines of conditionally immortalized brown preadipocytes (iBPAs) of mouse and human origin were generated. Conditional immortalization was achieved by doxycycline-controlled expression of simian virus 40 large tumor antigen (LT) with a repressor-based Tet-On system. In the presence of doxycycline, both the murine and human cell lines showed long-term proliferation capacity with a population doubling time of ~28 h. After switching off LT expression by doxycycline removal and exposure to adipogenic differentiation medium, cells from both species acquired brown adipocyte properties. This was evidenced by the accumulation of multilocular lipid droplets, the upregulation of brown adipocyte markers including uncoupling protein 1 and an increase in lipolysis and oxygen consumption following adrenergic stimulation. Switching off LT expression before the onset of adipogenic differentiation was only critical for inducing adipogenesis in the human iBPAs, while their murine counterparts showed adipogenesis upon exposure to the adipogenic differentiation cocktail regardless of LT expression. When switched to proliferation medium, cultures of adipogenically differentiated human iBPAs de-differentiated and resumed cell division without losing their adipogenic capacity. We suggest that iBPAs represent an easy-to-use model for fundamental and applied research into BAT offering unique experimental opportunities due to their capacity to switch between proliferative and differentiated states.