RESUMO
The tumor suppressor phosphatase and tensin homolog (PTEN) negatively regulates the insulin signaling pathway. Germline PTEN pathogenic variants cause PTEN hamartoma tumor syndrome (PHTS), associated with lipoma development in children. Adipose progenitor cells (APCs) lose their capacity to differentiate into adipocytes during continuous culture, whereas APCs from lipomas of patients with PHTS retain their adipogenic potential over a prolonged period. It remains unclear which mechanisms trigger this aberrant adipose tissue growth. To investigate the role of PTEN in adipose tissue development, we performed functional assays and RNA-Seq of control and PTEN knockdown APCs. Reduction of PTEN levels using siRNA or CRISPR led to enhanced proliferation and differentiation of APCs. Forkhead box protein O1 (FOXO1) transcriptional activity is known to be regulated by insulin signaling, and FOXO1 was downregulated at the mRNA level while its inactivation through phosphorylation increased. FOXO1 phosphorylation initiates the expression of the lipogenesis-activating transcription factor sterol regulatory element-binding protein 1 (SREBP1). SREBP1 levels were higher after PTEN knockdown and may account for the observed enhanced adipogenesis. To validate this, we overexpressed constitutively active FOXO1 in PTEN CRISPR cells and found reduced adipogenesis, accompanied by SREBP1 downregulation. We observed that PTEN CRISPR cells showed less senescence compared with controls and the senescence marker CDKN1A (p21) was downregulated in PTEN knockdown cells. Cellular senescence was the most significantly enriched pathway found in RNA-Seq of PTEN knockdown versus control cells. These results provide evidence that PTEN is involved in the regulation of APC proliferation, differentiation, and senescence, thereby contributing to aberrant adipose tissue growth in patients with PHTS.
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Tecido Adiposo/patologia , Diferenciação Celular , Proliferação de Células , Senescência Celular , Lipoma/patologia , Células-Tronco Mesenquimais/patologia , PTEN Fosfo-Hidrolase/metabolismo , Tecido Adiposo/metabolismo , Células Cultivadas , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Humanos , Lipoma/metabolismo , Células-Tronco Mesenquimais/metabolismo , PTEN Fosfo-Hidrolase/genética , Transdução de SinaisRESUMO
Small integral membrane protein 10 like 1 (SMIM10L1) was identified by RNA sequencing as the most significantly downregulated gene in Phosphatase and Tensin Homologue (PTEN) knockdown adipose progenitor cells (APCs). PTEN is a tumor suppressor that antagonizes the growth promoting Phosphoinositide 3-kinase (PI3K)/AKT/mechanistic Target of Rapamycin (mTOR) cascade. Diseases caused by germline pathogenic variants in PTEN are summarized as PTEN Hamartoma Tumor Syndrome (PHTS). This overgrowth syndrome is associated with lipoma formation, especially in pediatric patients. The mechanisms underlying this adipose tissue dysfunction remain elusive. We observed that SMIM10L1 downregulation in APCs led to an enhanced adipocyte differentiation in two- and three-dimensional cell culture and increased expression of adipogenesis markers. Furthermore, SMIM10L1 knockdown cells showed a decreased expression of PTEN, pointing to a mutual crosstalk between PTEN and SMIM10L1. In line with these observations, SMIM10L1 knockdown cells showed increased activation of PI3K/AKT/mTOR signaling and concomitantly increased expression of the adipogenic transcription factor SREBP1. We computationally predicted an α-helical structure and membrane association of SMIM10L1. These results support a specific role for SMIM10L1 in regulating adipogenesis, potentially by increasing PI3K/AKT/mTOR signaling, which might be conducive to lipoma formation in pediatric patients with PHTS.
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Síndrome do Hamartoma Múltiplo , Lipoma , Criança , Humanos , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Regulação para Baixo , Síndrome do Hamartoma Múltiplo/genética , Lipoma/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Células-Tronco/metabolismo , Serina-Treonina Quinases TOR/metabolismoRESUMO
PURPOSE: Adipokines may play an important role in the complex etiology of human obesity and its metabolic complications. Here, we analyzed the relationship between 15 adipokines, eating behavior and body-mass index (BMI). METHODS: The study included 557 participants of the Sorbs (62.1% women, 37.9% men) and 3101 participants of the population-based LIFE-Adult cohorts (53.4% women, 46.4% men) who completed the German version of the Three-Factor-Eating Questionnaire to assess the eating behavior types cognitive restraint, disinhibition and hunger. Serum levels of 15 adipokines, including adiponectin, adipocyte fatty acid-binding protein (AFABP), angiopoietin-related growth factor (AGF), chemerin, fibroblast growth factor (FGF)-19, FGF-21, FGF-23, insulin-like growth factor (IGF)-1, interleukin (IL) 10, irisin, progranulin, vaspin, pro-neurotensin (pro-NT), pro-enkephalin (PENK) and leptin were measured. Based on significant correlations between several adipokines with different eating behavior items and BMI, we conducted mediation analyses, considering the eating behavior items as potential mediation variable towards BMI. RESULTS: Here, we found that the positive association between chemerin, AFABP or leptin and BMI in Sorbian women was mediated by higher restraint or disinhibited eating, respectively. Additionally, in Sorbian women, the negative relation between IGF-1 and BMI was mediated by higher disinhibition and the positive link between AGF and BMI by lower disinhibition. In Sorbian men, the negative relationship between PENK and BMI was mediated by lower disinhibition and hunger, whereas the negative relation between IGF-1 and BMI was mediated by higher hunger. In the LIFE-Adult women´s cohort, associations between chemerin and BMI were mediated by decreased hunger or disinhibition, respectively, whereas relations between PENK and BMI were fully mediated by decreased disinhibition. CONCLUSION: Our study suggests that adipokines such as PENK, IGF-1, chemerin, AGF, AFABP and leptin might affect the development of obesity by directly modifying individual eating behavior. Given the observational nature of the study, future experimental or mechanistic work is warranted.
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Tecido Adiposo , Obesidade , Adulto , Índice de Massa Corporal , Comportamento Alimentar/psicologia , Feminino , Humanos , Fome , MasculinoRESUMO
GRB14/COBLL1 locus has been shown to be associated with body fat distribution (FD), but neither the causal gene nor its role in metabolic diseases has been elucidated. We hypothesize that GRB14/COBLL1 may act as the causal genes for FD-related SNPs (rs10195252 and rs6738627), and that they may be regulated by SNP to effect obesity-related metabolic traits. We genotyped rs10195252 and rs6738627 in 2860 subjects with metabolic phenotypes. In a subgroup of 560 subjects, we analyzed GRB14/COBLL1 gene expression in paired visceral and subcutaneous adipose tissue (AT) samples. Mediation analyses were used to determine the causal relationship between SNPs, AT GRB14/COBLL1 mRNA expression, and obesity-related traits. In vitro gene knockdown of Grb14/Cobll1 was used to test their role in adipogenesis. Both gene expressions in AT are correlated with waist circumference. Visceral GRB14 mRNA expression is associated with FPG and HbA1c. Both SNPs are associated with triglycerides, FPG, and leptin levels. Rs10195252 is associated with HbA1c and seems to be mediated by visceral AT GRB14 mRNA expression. Our data support the role of the GRB14/COBLL1 gene expression in body FD and its locus in metabolic sequelae: in particular, lipid metabolism and glucose homeostasis, which is likely mediated by AT GRB14 transcript levels.
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Tecido Adiposo , Obesidade , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Tecido Adiposo/metabolismo , Índice de Massa Corporal , Hemoglobinas Glicadas/metabolismo , Humanos , Obesidade/genética , Obesidade/metabolismo , RNA Mensageiro/metabolismo , Fatores de Transcrição/metabolismo , Relação Cintura-QuadrilRESUMO
INTRODUCTION: The polyphenol resveratrol has been suggested to exert beneficial effects on memory and the aging hippocampus due to calorie-restriction mimicking effects. However, the evidence based on human interventional studies is scarce. We therefore aimed to determine the effects of resveratrol on memory performance, and to identify potential underlying mechanisms using a broad array of blood-based biomarkers as well as hippocampus connectivity and microstructure assessed with ultra-high field magnetic resonance imaging (UHF-MRI). METHODS: In this double-blind, randomized controlled trial, 60 elderly participants (60-79 years) with a wide body-mass index (BMI) range of 21-37 kg/m2 were randomized to receive either resveratrol (200â¯mg/day) or placebo for 26 weeks (registered at ClinicalTrials.gov: NCT02621554). Baseline and follow-up assessments included the California Verbal Learning Task (CVLT, main outcome), the ModBent task, anthropometry, markers of glucose and lipid metabolism, inflammation and neurotrophins derived from fasting blood, multimodal neuroimaging at 3 and 7â¯T, and questionnaires to assess confounding factors. RESULTS: Multivariate repeated-measures ANOVA did not detect significant time by group effects for CVLT performance. There was a trend for preserved pattern recognition memory after resveratrol, while performance decreased in the placebo group (n.s., pâ¯=â¯0.07). Further exploratory analyses showed increases in both groups over time in body fat, cholesterol, fasting glucose, interleukin 6, high sensitive C-reactive protein, tumor necrosis factor alpha and in mean diffusivity of the subiculum and presubiculum, as well as decreases in physical activity, brain-derived neurotrophic factor and insulin-like growth factor 1â¯at follow-up, which were partly more pronounced after resveratrol. DISCUSSION: This interventional study failed to show significant improvements in verbal memory after 6 months of resveratrol in healthy elderly with a wide BMI range. A non-significant trend emerged for positive effects on pattern recognition memory, while possible confounding effects of unfavorable changes in lifestyle behavior, neurotrophins and inflammatory markers occurred. Our findings also indicate the feasibility to detect (un)healthy aging-related changes in measures of hippocampus microstructure after 6 months using 7T diffusion MRI. More studies incorporating a longer duration and larger sample size are needed to determine if resveratrol enhances memory performance in healthy older adults.
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Hipocampo/efeitos dos fármacos , Memória/efeitos dos fármacos , Resveratrol/administração & dosagem , Idoso , Mapeamento Encefálico , Método Duplo-Cego , Feminino , Hipocampo/anatomia & histologia , Hipocampo/fisiologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Memória/fisiologia , Pessoa de Meia-Idade , Vias Neurais/anatomia & histologia , Vias Neurais/fisiologia , Testes Neuropsicológicos , Reconhecimento Fisiológico de Modelo/efeitos dos fármacos , Reconhecimento Fisiológico de Modelo/fisiologiaRESUMO
OBJECTIVE: The current study investigates potential pathways from socio-economic status (SES) to BMI in the adult population, considering psychological domains of eating behaviour (restrained eating, uncontrolled eating, emotional eating) as potential mediators stratified for sex. DESIGN: Data were derived from the population-based cross-sectional LIFE-Adult-Study. Parallel-mediation models were conducted to obtain the total, direct and indirect effects of psychological eating behaviour domains on the association between SES and BMI for men and for women. SETTING: Leipzig, Germany. SUBJECTS: We studied 5935 participants aged 18 to 79 years. RESULTS: Uncontrolled eating mediated the association between SES and BMI in men only and restrained eating in both men and women. Emotional eating did not act as mediator in this relationship. The total effect of eating behaviour domains on the association between SES and BMI was estimated as ß=-0·03 (se 0·02; 95 % CI -0·062, -0·003) in men and ß=-0·18 (se 0·02; 95 % CI -0·217, -0·138) in women. CONCLUSIONS: Our findings do not indicate a strong overall mediation effect of the eating behaviour domains restrained eating, uncontrolled eating and emotional eating on the association between SES and BMI. Further research on other pathways of this association is strongly recommended. Importantly, our findings indicate that, independent from one's social position, focusing on psychological aspects in weight reduction might be a promising approach.
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Índice de Massa Corporal , Dieta/psicologia , Comportamento Alimentar/psicologia , Comportamentos Relacionados com a Saúde , Fatores Socioeconômicos , Adolescente , Adulto , Idoso , Estudos Transversais , Feminino , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Adulto JovemRESUMO
Chemerin is an adipokine proposed to link obesity and chronic inflammation of adipose tissue. Genetic factors determining chemerin release from adipose tissue are yet unknown. We conducted a meta-analysis of genome-wide association studies (GWAS) for serum chemerin in three independent cohorts from Europe: Sorbs and KORA from Germany and PPP-Botnia from Finland (total Nâ=â2,791). In addition, we measured mRNA expression of genes within the associated loci in peripheral mononuclear cells by micro-arrays, and within adipose tissue by quantitative RT-PCR and performed mRNA expression quantitative trait and expression-chemerin association studies to functionally substantiate our loci. Heritability estimate of circulating chemerin levels was 16.2% in the Sorbs cohort. Thirty single nucleotide polymorphisms (SNPs) at chromosome 7 within the retinoic acid receptor responder 2 (RARRES2)/Leucine Rich Repeat Containing (LRRC61) locus reached genome-wide significance (p<5.0×10-8) in the meta-analysis (the strongest evidence for association at rs7806429 with pâ=â7.8×10-14, betaâ=â-0.067, explained variance 2.0%). All other SNPs within the cluster were in linkage disequilibrium with rs7806429 (minimum r2â=â0.43 in the Sorbs cohort). The results of the subgroup analyses of males and females were consistent with the results found in the total cohort. No significant SNP-sex interaction was observed. rs7806429 was associated with mRNA expression of RARRES2 in visceral adipose tissue in women (p<0.05 after adjusting for age and body mass index). In conclusion, the present meta-GWAS combined with mRNA expression studies highlights the role of genetic variation in the RARRES2 locus in the regulation of circulating chemerin concentrations.
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Quimiocinas/sangue , Quimiocinas/genética , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Peptídeos e Proteínas de Sinalização Intercelular/genética , Quimiocinas/metabolismo , Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Gordura Intra-Abdominal/metabolismo , Obesidade/sangue , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Gordura Subcutânea/metabolismoRESUMO
Many diseases nowadays are assumed to be genetically determined. Therefore, many knockout mouse models have been established and are widely used. Unfortunately, nutrition (in particular the fat content of food) is often neglected in studies on these disease models. In this study the effects of nutrition on the lipid (triacylglycerol, TAG) compositions of different mouse adipose tissues were investigated. Mice were subjected to different diets [high fat (HF) vs. standard diet (SD)] and different adipose tissue samples (brown, visceral, and subcutaneous fat) were isolated after 12 weeks. Subsequent to lipid extraction, the organic extracts were analyzed by mass spectrometry (MALDI and ESI), high-resolution (1)H and (31)P NMR spectroscopy, high-performance thin-layer chromatography (HPTLC), and gas chromatography (GC). In adipose tissue of mice fed with HF diet, (a) decreased double bond contents and (b) decreased fatty acyl chain lengths of tissue TAGs were observed; this trend could be concomitantly monitored by all methods used. However, the adipose tissue still contained significant amounts of slightly unsaturated fatty acyl residues (18:1). Thus, a certain double bond content seems necessary to maintain the properties of adipose tissues.
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Tecido Adiposo/química , Dieta Hiperlipídica , Lipídeos/análise , Triglicerídeos/análise , Tecido Adiposo/metabolismo , Animais , Cromatografia Gasosa , Cromatografia em Camada Fina , Gorduras na Dieta/análise , Gorduras na Dieta/metabolismo , Ácidos Graxos Insaturados/análise , Ácidos Graxos Insaturados/metabolismo , Metabolismo dos Lipídeos , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Triglicerídeos/metabolismoRESUMO
The 'Fragebogen zum Essverhalten' (FEV) is the German version of the Three-factor-Eating-Questionnaire (TFEQ). This questionnaire covers three domains of eating behaviour ('cognitive restraint', 'disinhibition' and 'hunger') as well as common problems (e.g. craving for sweets). So far, there is a lack of normative data of the FEV especially for the middle-aged and older population. Aim of this study therefore was to provide age- and gender-specific norms of the FEV for the general population aged 40-79 years. We studied 3144 participants of the ongoing large community-based Leipzig Research Center for Civilization Diseases (LIFE) Health Care Study. We provided age- (four age groups: 40-49, 50-59, 60-69, and 70-79 years) and gender-specific percentile ranks and T-scores for the three domains of the FEV as well as age- and gender-specific frequencies of the common problems in eating behaviour. Females scored significantly higher than males in all three domains of the FEV (p < 0.001). Older individuals showed significantly higher mean scores than the younger ones in the domain of cognitive restraint, but lower mean scores in disinhibition and hunger (p < 0.001). 45.1% of the males and 69.9% of the females reported specific problems in eating. The main problem in both genders was craving for sweets (38.6%). Eating in response to stress was mostly reported in younger individuals. The present study offers current normative data for the FEV in the middle-aged and older general population that can be applied in clinical and non-clinical settings. Information on eating behaviour can be helpful in understanding body weight modulation, and thus, may help to improve interventive and preventive programmes for overweight, obesity, and eating disorders.
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Fissura , Dieta , Comportamento Alimentar , Fome , Inibição Psicológica , Autocontrole , Adulto , Fatores Etários , Idoso , Sacarose Alimentar , Feminino , Preferências Alimentares , Identidade de Gênero , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/etiologia , Obesidade/prevenção & controle , Fatores Sexuais , Inquéritos e QuestionáriosRESUMO
Although numerous genes are known to regulate serum lipid traits, identified variants explain only a small proportion of the expected heritability. We intended to identify further genetic variants associated with lipid phenotypes in a self-contained population of Sorbs in Germany. We performed a genome-wide association study (GWAS) on LDL-cholesterol, HDL-cholesterol (HDL-C), and triglyceride (TG) levels in 839 Sorbs. All single-nucleotide polymorphisms with a P value <0.01 were subjected to a meta-analysis, including an independent Swedish cohort (Diabetes Genetics Initiative; n = â¼3,100). Novel association signals with the strongest effects were subjected to replication studies in an additional German cohort (Berlin, n = 2,031). In the initial GWAS in the Sorbs, we identified 14 loci associated with lipid phenotypes reaching P values <10â»5 and confirmed significant effects for 18 previously reported loci. The combined meta-analysis of the three study cohorts (n(HDL) = 6041; n(LDL) = 5,995; n(TG) = 6,087) revealed a novel association for a variant in THOC5 (rs8135828) with serum HDL-C levels (P = 1.78 × 10â»7; Z-score = -5.221). Consistently, the variant was also associated with circulating APOA1 levels in Sorbs. The small interfering RNA-mediated mRNA silencing of THOC5 in HepG2 cells resulted in lower mRNA levels of APOA1, SCARB1, and ABCG8 (all P < 0.05). We propose THOC5 to be a novel gene involved in the regulation of serum HDL-C levels.
Assuntos
HDL-Colesterol/metabolismo , Proteínas Nucleares/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Alemanha/etnologia , Células Hep G2 , Humanos , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Adulto JovemRESUMO
BACKGROUND: The complex process of development of the pituitary gland is regulated by a number of signalling molecules and transcription factors. Mutations in these factors have been identified in rare cases of congenital hypopituitarism but for most subjects with combined pituitary hormone deficiency (CPHD) genetic causes are unknown. Bone morphogenetic proteins (BMPs) affect induction and growth of the pituitary primordium and thus represent plausible candidates for mutational screening of patients with CPHD. METHODS: We sequenced BMP2, 4 and 7 in 19 subjects with CPHD. For validation purposes, novel genetic variants were genotyped in 1046 healthy subjects. Additionally, potential functional relevance for most promising variants has been assessed by phylogenetic analyses and prediction of effects on protein structure. RESULTS: Sequencing revealed two novel variants and confirmed 30 previously known polymorphisms and mutations in BMP2, 4 and 7. Although phylogenetic analyses indicated that these variants map within strongly conserved gene regions, there was no direct support for their impact on protein structure when applying predictive bioinformatics tools. CONCLUSIONS: A mutation in the BMP4 coding region resulting in an amino acid exchange (p.Arg300Pro) appeared most interesting among the identified variants. Further functional analyses are required to ultimately map the relevance of these novel variants in CPHD.
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Adipokines provide an outstanding role in the comprehensive etiology of obesity and may link adipose tissue dysfunction to further metabolic and cardiovascular complications. Although several adipokines have been identified in terms of their physiological roles, many regulatory circuits remain unclear and translation from experimental studies to clinical applications has yet to occur. Nevertheless, due to their complex metabolic properties, adipokines offer immense potential for their use both as obesity-associated biomarkers and as relevant treatment strategies for overweight, obesity and metabolic comorbidities. To provide an overview of the current clinical use of adipokines, this review summarizes clinical studies investigating the potential of various adipokines with respect to diagnostic and therapeutic treatment strategies for obesity and linked metabolic disorders. Furthermore, an overview of adipokines, for which a potential for clinical use has been demonstrated in experimental studies to date, will be presented. In particular, promising data revealed that fibroblast growth factor (FGF)-19, FGF-21 and leptin offer great potential for future clinical application in the treatment of obesity and related comorbidities. Based on data from animal studies or other clinical applications in addition to obesity, adipokines including adiponectin, vaspin, resistin, chemerin, visfatin, bone morphogenetic protein 7 (BMP-7) and tumor necrosis factor alpha (TNF-α) provide potential for human clinical application.
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Adipose tissue inflammation and insulin resistance are hallmarks in the development of metabolic diseases resulting from overweight and obesity, such as type 2 diabetes and non-alcoholic fatty liver disease. In obesity, adipocytes predominantly secrete proinflammatory adipokines that further promote adipose tissue dysfunction with negative effects on local and systemic insulin sensitivity. Expression of the serpin vaspin (SERPINA12) is also increased in obesity and type 2 diabetes, but exhibits compensatory roles in inflammation and insulin resistance. This has in part been demonstrated using vaspin-transgenic mice. We here report a new mouse line (h-vaspinTG) with transgenic expression of human vaspin in adipose tissue that reaches vaspin concentrations three orders of magnitude higher than wild type controls (>200 ng/ml). Phenotyping under chow and high-fat diet conditions included glucose-tolerance tests, measurements of energy expenditure and circulating parameters, adipose tissue and liver histology. Also, ex vivo glucose uptake in isolated adipocytes and skeletal muscle was analyzed in h-vaspinTG and littermate controls. The results confirmed previous findings, revealing a strong reduction in diet-induced weight gain, fat mass, hyperinsulinemia, -glycemia and -cholesterolemia as well as fatty liver. Insulin sensitivity in adipose tissue and muscle was not altered. The h-vaspinTG mice showed increased energy expenditure under high fat diet conditions, that may explain reduced weight gain and overall metabolic improvements. In conclusion, this novel human vaspin-transgenic mouse line will be a valuable research tool to delineate whole-body, tissue- and cell-specific effects of vaspin in health and disease.
Assuntos
Diabetes Mellitus Tipo 2 , Resistência à Insulina , Hepatopatia Gordurosa não Alcoólica , Serpinas , Humanos , Camundongos , Animais , Dieta Hiperlipídica/efeitos adversos , Camundongos Transgênicos , Obesidade/genética , Obesidade/metabolismo , Inflamação/metabolismo , Aumento de Peso , Metabolismo Energético/genética , Serpinas/genética , Adipocinas/metabolismoRESUMO
Transforming growth factor beta-1 (TGFß1) is an adipokine secreted from adipose tissue, placental tissue and immune cells with a role in cell proliferation, cell apoptosis and angiogenic proliferation. The role of TGFß1 in pregnancy and child growth and the source of cord TGFß1 are yet unknown. In this study, we sought to clarify the correlation of TGFß1 levels with parameters of intrauterine growth and child growth during the first year of life, and to determine whether their source is primarily of fetal or maternal origin. Serum samples and anthropometric measurements were obtained from the LIFE Child cohort of 79 healthy mother-child pairs. Measurements were conducted using enzyme-linked immunosorbent assays. Statistical analyses including Mann-Whitney U-test, correlation analyses and linear regression analyses were performed using GraphPad Prism and R. TGFß1 levels were significantly higher in cord than in maternal serum, suggesting a fetal origin. Multivariate regression analyses revealed strong positive associations between cord TGFß1 levels at birth and child weight at U6. Furthermore, cord TGFß1 was significantly correlated with child weight at approximately one year of age. An increase of 10,000 pg/mL in cord TGFß1 concentrations at birth was associated with a higher body weight of 201 g at roughly one year of age when adjusted for sex.
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OBJECTIVE: Vaspin (visceral adipose tissue derived serine protease inhibitor, SERPINA12) is associated with obesity-related metabolic traits, but its causative role is still elusive. The role of genetics in serum vaspin variability to establish its causal relationship with metabolically relevant traits was investigated. METHODS: A meta-analysis of genome-wide association studies for serum vaspin from six independent cohorts (N = 7446) was conducted. Potential functional variants of vaspin were included in Mendelian randomization (MR) analyses to assess possible causal pathways between vaspin and homeostasis model assessment and lipid traits. To further validate the MR analyses, data from Genotype-Tissue Expression (GTEx) were analyzed, db/db mice were treated with vaspin, and serum lipids were measured. RESULTS: A total of 468 genetic variants represented by five independent variants (rs7141073, rs1956709, rs4905216, rs61978267, rs73338689) within the vaspin locus were associated with serum vaspin (all p < 5×10-8 , explained variance 16.8%). MR analyses revealed causal relationships between serum vaspin and triglycerides, low-density lipoprotein, and total cholesterol. Gene expression correlation analyses suggested that genes, highly correlated with vaspin expression in adipose tissue, are enriched in lipid metabolic processes. Finally, in vivo vaspin treatment reduced serum triglycerides in obese db/db mice. CONCLUSIONS: The data show that serum vaspin is strongly determined by genetic variants within vaspin, which further highlight vaspin's causal role in lipid metabolism.
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Metabolismo dos Lipídeos , Serpinas , Animais , Camundongos , Adipocinas/metabolismo , Estudo de Associação Genômica Ampla , Metabolismo dos Lipídeos/genética , Obesidade/metabolismo , Serpinas/sangue , Serpinas/genética , Triglicerídeos , HumanosRESUMO
The hepatitis C virus (HCV)-related bovine hepacivirus (BovHepV) can cause acute as well as persistent infections in cattle. The true clinical relevance of the virus is not yet known. As reliable antibody detection methods are lacking and prevalence studies have only been conducted in cattle and few countries to date, the true distribution, genetic diversity, and host range is probably greatly underestimated. In this study, we applied several RT-PCR methods and a nano-luciferase-based immunoprecipitation system (LIPS) assay to analyze bovine serum samples from Bulgaria as well as wild ruminant sera from Germany and the Czech Republic. Using these methods, BovHepV infections were confirmed in Bulgarian cattle, with viral genomes detected in 6.9% and serological reactions against the BovHepV NS3 helicase domain in 10% of bovine serum samples. Genetic analysis demonstrated co-circulation of highly diverse BovHepV strains in Bulgarian cattle, and three novel BovHepV subtypes within the genotype 1 could be defined. Furthermore, application of a nested RT-PCR led to the first description of a BovHepV variant (genotype 2) in a wild ruminant species. The results of this study significantly enhance our knowledge of BovHepV distribution, genetic diversity, and host range.
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Hepacivirus , Hepatite C , Animais , Bovinos , Genômica , Hepacivirus/genética , Especificidade de Hospedeiro , RuminantesRESUMO
Fibroblast growth factor 21 (FGF21) is a regulator of addictive behavior. Increasing evidence suggests an impact of FGF21 on eating behavior, food and drug cravings and on other adipokines like insulin-like growth factor 1 (IGF-1) or adiponectin. We investigated the association of serum FGF21 and genetic variants with aspects of food and drug craving and obesity related metabolic parameters including serum adipokine levels. Standardized questionnaires, blood samples and anthropometric data of the Sorbs cohort (n = 1046) were analyzed using SPSS. For genetic analyses, the FGF21-locus ±10 kb was genotyped and analyzed using PLINK. Validation was conducted in a second independent cohort (n = 704). FGF21 was significantly associated with alcohol and coffee consumption, smoking and eating behavior (disinhibition). We confirmed correlations of FGF21 serum levels with IGF-1, adiponectin, pro-enkephalin, adipocyte fatty-acid-binding protein, chemerin and progranulin. FGF21 genetic variants were associated with anthropometric and metabolic parameters, adipokines, food and drug craving while strongest evidence was seen with low-density lipoprotein cholesterol (LDL-C). We highlight the potential role of FGF21 in food and drug cravings and provide new insights regarding the link of FGF21 with other adipokines as well as with metabolic traits, in particular those related to lipid metabolism (LDL-C).
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Subcutaneous (sc) and visceral (vis) adipose tissue (AT) contribute to the variability in pathophysiological consequences of obesity and adverse fat distribution. To gain insights into the molecular mechanisms distinguishing vis and sc fat, we compared the transcriptome during differentiation of immortalized adipocytes from murine epididymal (epi) and inguinal (ing) AT. RNA was extracted on different days of adipogenesis (-2, 0, 2, 4, 6, 8) and analyzed using Clariom™ D mouse assays (Affymetrix) covering >214,900 transcripts in >66,100 genes. Transcript Time Course Analysis revealed 137 differentially expressed genes. The top genes with most divergent expression dynamics included developmental genes like Alx1, Lhx8, Irx1/2, Hoxc10, Hoxa5/10, and Tbx5/15. According to pathway analysis the majority of the genes were enriched in pathways related to AT development. Finally, in paired samples of human vis and sc AT (N = 63), several of these genes exhibited depot-specific variability in expression which correlated closely with body mass index and/or waist-to-hip ratio. In conclusion, intrinsically programmed differences in gene expression patterns during adipogenesis suggest that fat depot specific regulation of adipogenesis contributes to individual risk of obesity.
Assuntos
Adipogenia/genética , Tecido Adiposo/crescimento & desenvolvimento , Tecido Adiposo/metabolismo , Obesidade , Adulto , Idoso , Animais , Animais Recém-Nascidos , Estudos de Casos e Controles , Células Cultivadas , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Magreza/genética , Magreza/metabolismo , Magreza/patologiaRESUMO
The microbial carbon and hydrogen isotope fractionation of benzene under sulfate-reducing conditions was investigated within systems of increasing complexity: (i) batch laboratory microcosms, (ii) a groundwater-percolated column system, and (iii) an aquifer transect. Recent molecular biological studies indicate that, at least in the laboratory microcosms and the column system, benzene is degraded by similar bacterial communities. Carbon and hydrogen enrichment factors (epsilon(C), epsilon(H)) obtained from laboratory microcosms and from the column study varied significantly although experiments were performed under similar redox and temperature conditions. Thus, enrichment factors for only a single element could not be used to distinguish benzene degradation under sulfate-reducing conditions from other redox conditions. In contrast, using correlation of changes of hydrogen vs. carbon isotope ratios (Lambda = Delta delta(2)H/Delta delta(13)C), similar Lambda-values were derived for the benzene biodegradation under sulfate-reducing conditions in all three experimental systems (Lambda(laboratory microcosms) = 23 +/- 5, Lambda(column) = 28 +/- 3, Lambda(aquifer) = 24 +/- 2), showing the robustness of the two-dimensional compound-specific stable isotope analysis (2D-CSIA) for elucidating distinct biodegradation pathways. Comparing carbon and hydrogen isotope fractionation data from recent studies, an overlap in Lambda-values was observed for benzene biodegradation under sulfate-reducing (Lambda = 23 +/- 5 to Lambda = 29 +/- 3) and methanogenic (Lambda = 28 +/- 1 to Lambda = 39 +/- 5) conditions, indicating a similar initial benzene reaction mechanism for both electron-acceptor conditions.
Assuntos
Bactérias/metabolismo , Benzeno/análise , Isótopos de Carbono/análise , Deutério/análise , Sulfatos/química , Poluentes Químicos da Água/análise , Bactérias/química , Benzeno/metabolismo , Biodegradação Ambiental , Isótopos de Carbono/metabolismo , Deutério/metabolismo , Oxirredução , Sulfatos/metabolismo , Poluentes Químicos da Água/metabolismoRESUMO
VASPIN, visceral adipose tissue-derived serpin, is an adipokine ameliorating insulin resistance in obesity. Here, we investigated the role of VASPIN and its genetic variants in lipid metabolism. We measured serum VASPIN concentrations by ELISA in 823 metabolically well-characterized Caucasian subjects (Sorbs from Germany). Furthermore, we genotyped 30 representative single nucleotide polymorphisms (SNP) in two independent cohorts with metabolic phenotyping, the Sorbs (N = 823) and Leipzig (N = 919), and conducted genotype-phenotype association analyses. Circulating VASPIN strongly correlated with triacylglycerol levels (TAG; p = 1.079 × 10-11 ), and moderately with apolipoprotein A1 and low-density lipoprotein cholesterol (p = 0.026). Genetic variants in VASPIN were nominally associated with cholesterol, high-density and low-density lipoprotein (HDL-chol, LDL-chol), lipoprotein A, and apolipoprotein B as well as with TAG and free fatty acids (all p < 0.05 adjusted for age, sex, and body mass index [BMI]). Mendelian randomization analysis using VASPIN SNP as an instrumental variable showed borderline influence of VASPIN on LDL-chol levels (p = 0.05). Associations of VASPIN and its genetic variation with metabolic traits suggest a role of VASPIN in human lipid metabolism.