We are pleased to present the first and second editions of this Special Issue, titled "Molecular and Genetic Aspects of SARS-CoV-2 Infection and COVID-19 Disease", of the International Journal of Molecular Sciences [...].
COVID-19 , SARS-CoV-2 , COVID-19/genetics , COVID-19/virology , Humans , SARS-CoV-2/genetics
Non-alcoholic fatty liver disease (NAFLD) is a growing health problem due to the increased obesity rates, among other factors. In its more severe stage (NASH), inflammation, hepatocellular ballooning and fibrosis are present in the liver, which can further evolve to total liver dysfunction or even hepatocarcinoma. As a metabolic disease, is associated to environmental factors such as diet and lifestyle conditions, which in turn can influence the epigenetic landscape of the cells, affecting to the gene expression profile and chromatin organization. In this study we performed ATAC-sequencing and RNA-sequencing to interrogate the chromatin status of liver biopsies in subjects with and without NASH and its effects on RNA transcription and NASH etiology. NASH subjects showed transcriptional downregulation for lipid and glucose metabolic pathways (e.g., ABC transporters, AMPK, FoxO or insulin pathways). A total of 229 genes were differentially enriched (ATAC and mRNA) in NASH, which were mainly related to lipid transport activity, nuclear receptor-binding, dicarboxylic acid transporter, and PPARA lipid regulation. Interpolation of ATAC data with known liver enhancer regions showed differential openness at 8 enhancers, some linked to genes involved in lipid metabolism, (i.e., FASN) and glucose homeostasis (i.e., GCGR). In conclusion, the chromatin landscape is altered in NASH patients compared to patients without this liver condition. This alteration might cause mRNA changes explaining, at least partially, the etiology and pathophysiology of the disease.
Epigenesis, Genetic , Non-alcoholic Fatty Liver Disease , Humans , Non-alcoholic Fatty Liver Disease/genetics , Non-alcoholic Fatty Liver Disease/metabolism , Non-alcoholic Fatty Liver Disease/pathology , Liver/metabolism , Liver/pathology , Male , Female , Lipid Metabolism/genetics , Middle Aged , Chromatin/metabolism , Chromatin/genetics , RNA/genetics , Adult , RNA, Messenger/genetics , RNA, Messenger/metabolism , Gene Expression Regulation
BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely tied to obesity. The degree ranges from steatosis (MASL) and steatohepatitis (MASH) to liver cirrhosis. PCSK9 controls cholesterol and lipid particle transport to the liver. PCSK9 might interfere with the pathophysiology of MASLD and bariatric surgery (BS) outcomes of patients with MASLD. OBJECTIVES: Evaluate the relationship between serum and hepatic PCSK9 levels with the degree of MASLD and the metabolic outcome of BS. SETTING: University Hospital, Spain. METHODS: A total of 110 patients with obesity undergoing BS were classified according to liver histology as controls, MAS, and MASH. PCSK9 levels in serum were measured before and 6 months after BS using enzyme-linked immunosorbent assay. PCSK9 protein and mRNA levels in liver tissue were analyzed by immunohistochemistry and reverse transcriptase-polymerase chain reaction, respectively. RESULTS: Hepatic PCSK9 protein levels were diminished in MASL and MASH compared with patients without MASLD and showed a strong negative association with MASLD severity scores. Liver PCSK9 mRNA was higher in MASH compared with controls and MASL and showed positive associations with MASLD severity scores. There were no differences in serum PCSK9 pre or postBS between the groups. Pre- and postsurgery serum PCSK9 positively correlated with cholesterol fold-changes and body mass index (BMI), cholesterol, and low-density lipoprotein -cholesterol fold-changes, respectively. PCSK9 fold-change positively correlated with BMI changes and was the sole variable explaining BMI fold changes in a regression model. CONCLUSIONS: PCSK9 mRNA and protein in the liver might be associated with the degree of MASLD. Serum PCSK9 may be associated with cholesterol and/or BMI fold changes. Serum changes of PCSK9 after BS could explain BMI loss outcome.
This letter praises a recent article in the World Journal of Clinical Cases (Roles of biochemistry data, lifestyle, and inflammation in identifying abnormal renal function in old Chinese), examining factors affecting abnormal renal function in elderly Chinese using advanced machine learning. It highlights the importance of uric acid, age, hemoglobin, body mass index, sport hours, and systolic blood pressure. The study's holistic approach, integrating lifestyle and inflammation, offers a nuanced understanding of chronic kidney disease risk factors. The letter suggests exploring mechanistic pathways of hyperuricemia, the link between anemia and renal function, and the connection between body mass index and estimated glomerular filtration rate. It advocates investigating physical activity's impact on renal health and the independent effects of blood pressure. The study significantly contributes to chronic kidney disease understanding, proposing avenues for further exploration and interventions. Commendations are extended to the authors and the journal.
Short-wave infrared (SWIR) fluorescence could become the new gold standard in optical imaging for biomedical applications due to important advantages such as lack of autofluorescence, weak photon absorption by blood and tissues, and reduced photon scattering coefficient. Therefore, contrary to the visible and NIR regions, tissues become translucent in the SWIR region. Nevertheless, the lack of bright and biocompatible probes is a key challenge that must be overcome to unlock the full potential of SWIR fluorescence. Although rare-earth-based core-shell nanocrystals appeared as promising SWIR probes, they suffer from limited photoluminescence quantum yield (PLQY). The lack of control over the atomic scale organization of such complex materials is one of the main barriers limiting their optical performance. Here, the growth of either homogeneous (α-NaYF4) or heterogeneous (CaF2) shell domains on optically-active α-NaYF4:Yb:Er (with and without Ce3+ co-doping) core nanocrystals is reported. The atomic scale organization can be controlled by preventing cation intermixing only in heterogeneous core-shell nanocrystals with a dramatic impact on the PLQY. The latter reached 50% at 60 mW/cm2; one of the highest reported PLQY values for sub-15 nm nanocrystals. The most efficient nanocrystals were utilized for in vivo imaging above 1450 nm.
[This corrects the article DOI: 10.1212/NXG.0000000000200079.].
Several studies indicate that the pandemic and associated confinement measures may have had an impact on mental health, producing the onset or persistence of symptoms such as stress, anxiety, depression, and fear. This systematic review aims to identify the factors influencing the onset or worsening of depressive symptoms during COVID-19-related confinement. Our systematic search produced 451 articles from selected databases, 398 of which were excluded based on established criteria, while 53 were selected for review. Most studies have reported an increase in the prevalence of depressive symptoms in the general population during the first weeks of confinement. The predominant risk factors associated with the appearance of depressive symptoms included female sex, low educational level, young age, economic difficulties, comorbidities, and a history of previous depressive episodes. People with a pre-existing diagnosis of depressive disorder generally experienced a worsening of their symptoms during confinement in most of the reviewed studies. Moreover, symptomatology persisted at higher levels post-confinement, without significant improvement despite relief in confinement measures. Therefore, ongoing evaluations of post-pandemic depressive symptoms are necessary to advance the knowledge of the relationship between pandemics and depression, allowing accurate conclusions and associations to be made.
Background and Objectives: Most patients with amyotrophic lateral sclerosis (ALS) lack a monogenic mutation. This study evaluates ALS cumulative genetic risk in an independent Michigan and Spanish replication cohort using polygenic scores. Methods: Participant samples from University of Michigan were genotyped and assayed for the chromosome 9 open reading frame 72 hexanucleotide expansion. Final cohort size was 219 ALS and 223 healthy controls after genotyping and participant filtering. Polygenic scores excluding the C9 region were generated using an independent ALS genome-wide association study (20,806 cases, 59,804 controls). Adjusted logistic regression and receiver operating characteristic curves evaluated the association and classification between polygenic scores and ALS status, respectively. Population attributable fractions and pathway analyses were conducted. An independent Spanish study sample (548 cases, 2,756 controls) was used for replication. Results: Polygenic scores constructed from 275 single-nucleotide variation (SNV) had the best model fit in the Michigan cohort. An SD increase in ALS polygenic score associated with 1.28 (95% CI 1.04-1.57) times higher odds of ALS with area under the curve of 0.663 vs a model without the ALS polygenic score (p value = 1 × 10-6). The population attributable fraction of the highest 20th percentile of ALS polygenic scores, relative to the lowest 80th percentile, was 4.1% of ALS cases. Genes annotated to this polygenic score enriched for important ALS pathomechanisms. Meta-analysis with the Spanish study, using a harmonized 132 single nucleotide variation polygenic score, yielded similar logistic regression findings (odds ratio: 1.13, 95% CI 1.04-1.23). Discussion: ALS polygenic scores can account for cumulative genetic risk in populations and reflect disease-relevant pathways. If further validated, this polygenic score will inform future ALS risk models.
INTRODUCTION: Although often overlooked in clinical settings, accumulation of persistent organic pollutants (POPs) in visceral adipose tissue (VAT) is thought to be a relevant risk factor for metabolic syndrome (MetS). METHODS: One hundred and seventeen patients undergoing non-oncological surgery were randomly recruited and classified as MetS + if presented 3 out of the 5 MetS components: waist circumference (WC), systolic and diastolic blood pressure (SBP and DBP, respectively), serum glucose, insulin, triglycerides (TG) and high-density lipoprotein (HDL) cholesterol levels, according International Diabetes Federation (IDF) criteria. Seventeen organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) were measured in adipose tissue samples. Linear, logistic and weighted quantile sum (WQS) regression models, adjusted for age and sex, were performed. RESULTS: One third of the participants were males (36.8%) with a median age of 44 years, showing clinical evidences of MetS (35.0%). Adjusted linear regression models showed that WC correlated positively with all OCP concentrations. Higher fasting serum glucose levels were related to higher HCB and γ-HCH concentrations. The remaining OCPs and PCBs were not associated with this MetS component. HCB was inversely associated with HDL cholesterol levels, while PCB-180 was positively associated. HCB and γ-HCH concentrations were also positively correlated with DBP and SBP levels. PCB-138 was also positively associated with SBP. Adjusted logistic models revealed that exposure to HCB and γ-HCH were associated with increased odds of MetS [ORs (95%CI) 1.53 (1.22-1.92) and 1.39 (1.10-1.76) respectively; p < 0.01]. No associations were observed for the remaining POPs. WQS models showed a positive and significant mixture effect of POPs on the odds of MetS (exp [beta] = 2.34; p < 0.001), with γ-HCH (52.9%), o,p'-DDT (26.9%) and HCB (19.7%) driving the association. CONCLUSIONS: Our findings support that POPs accumulated in VAT, specifically HCB and (gamma)-HCH, are associated with both isolated components and clinically diagnosed SMT.
Environmental Pollutants , Hydrocarbons, Chlorinated , Metabolic Syndrome , Pesticides , Polychlorinated Biphenyls , Middle Aged , Male , Adult , Humans , Female , Persistent Organic Pollutants , Environmental Exposure , Hexachlorocyclohexane , Cross-Sectional Studies , Environmental Pollutants/metabolism , Hydrocarbons, Chlorinated/analysis , Adipose Tissue/chemistry , Glucose
Growing evidence supports the importance of the p53 tumor suppressor in metabolism but the mechanisms underlying p53-mediated control of metabolism remain poorly understood. Here, we identify the multifunctional E4F1 protein as a key regulator of p53 metabolic functions in adipocytes. While E4F1 expression is upregulated during obesity, E4f1 inactivation in mouse adipose tissue results in a lean phenotype associated with insulin resistance and protection against induced obesity. Adipocytes lacking E4F1 activate a p53-dependent transcriptional program involved in lipid metabolism. The direct interaction between E4F1 and p53 and their co-recruitment to the Steaoryl-CoA Desaturase-1 locus play an important role to regulate monounsaturated fatty acids synthesis in adipocytes. Consistent with the role of this E4F1-p53-Steaoryl-CoA Desaturase-1 axis in adipocytes, p53 inactivation or diet complementation with oleate partly restore adiposity and improve insulin sensitivity in E4F1-deficient mice. Altogether, our findings identify a crosstalk between E4F1 and p53 in the control of lipid metabolism in adipocytes that is relevant to obesity and insulin resistance.
Adipocytes/metabolism , Adipose Tissue/metabolism , Obesity/genetics , Repressor Proteins/genetics , Stearoyl-CoA Desaturase/genetics , Tumor Suppressor Protein p53/genetics , Ubiquitin-Protein Ligases/genetics , Adipocytes/pathology , Adipose Tissue/pathology , Adult , Aged , Animals , Body Mass Index , Fatty Acids, Monounsaturated/metabolism , Female , Gene Expression Regulation , Humans , Insulin Resistance , Lipid Metabolism/genetics , Male , Mice , Mice, Knockout , Middle Aged , Obesity/metabolism , Obesity/pathology , Repressor Proteins/deficiency , Repressor Proteins/metabolism , Signal Transduction , Stearoyl-CoA Desaturase/metabolism , Tumor Suppressor Protein p53/metabolism , Ubiquitin-Protein Ligases/deficiency , Ubiquitin-Protein Ligases/metabolism
BACKGROUND: Adipose tissue (AT) dysfunction is involved in obesity-related comorbidities. Epigenetic alterations have been recently associated with AT deterioration in obesity conditions. In this work, we profiled the H3K4me3 histone mark in human AT, with special emphasis on the changes in the pattern of histone modification in obesity and insulin resistance (IR). Visceral AT (VAT) was collected and subjected to chromatin immunoprecipitation (ChIP) using anti-H3K4me3 antibody and then sequenced to obtain the H3K4me3 genome profile. RESULTS: We found that most of the H3K4me3 enriched regions were located in gene promoters of pathways related to AT biology and function. H3K4me3 enrichment at gene promoters was strongly related to higher mRNA levels. Differentially expressed genes in AT of patients classified as non-obese, obese with low IR, and obese with high IR could be regulated by differentially enriched H3K4me3; these genes encoded for pathways that could in part explain AT functioning during obesity and insulin resistance (e.g., extracellular matrix organization, PPARG signaling or inflammation). CONCLUSIONS: In conclusion, we emphasize the importance of the epigenetic mark H3K4me3 in VAT dysfunction in obesity and IR. The understanding of such mechanisms could give rise to the development of new epigenetic-based pharmacological strategies to ameliorate obesity-related comorbidities.
OBJECTIVE: Adipose tissue-derived stem cells (ASCs) might play an important role in adipose microenvironment remodelling during tissue expansion through their response to hypoxia. We examined the cytokine profiles of hypoxic visceral ASCs (hypox-visASCs) from subjects with different metabolic risk, the interactions between cytokines as well as the impact of TNFα-induced death in the behavior of surviving hypoxic subcutaneous ASCs (hypox-subASCs) both at bulk population and single-cell level. MATERIALS/METHODS: Visceral adipose tissue was processed to isolate the ASCs from 33 subjects grouped into normal weight, obese with and without metabolic syndrome. Multiplex assay was used to simultaneously measure multiple inflammatory, anti-inflammatory and angiogenic cytokines in hypox-visASCs from these patients and to elucidate cytokine profiles of hypox-subASCs upon stimulation with IL1ß or TNFα and after TNFα-induced death. qPCR and single-cell RNA-sequencing were also performed to elucidate transcriptional impact in surviving hypox-subASCs after TNFα-induced apoptosis. RESULTS: Hypox-visASCs from subjects without metabolic syndrome showed greater secretion levels of inflammatory, anti-inflammatory and angiogenic cytokines compared with those from patients with metabolic syndrome. While IL-1ß stimulation was sufficient to increase the secretion levels of these cytokines in hypox-subASCs, TNFα-induced apoptosis also increased their levels and impacted on the expression levels of extracellular matrix proteins, acetyl-CoA producing enzymes and redox-balance proteins in surviving hypox-subASCs. TNFα-induced apoptosis under different glucose concentrations caused selective impoverishment of cell clusters and differentially influenced gene expression profiles of surviving hypox-subASCs. CONCLUSIONS: Immunoregulatory and angiogenic functions of hypox-visASCs from patients with metabolic syndrome could be insufficient to promote healthy adipose tissue expansion. TNFα-induced apoptosis may impact on functionality of hypox-subASC populations, whose differential metabolic sensitivity to death could serve to manipulate individual populations selectively in order to elucidate their role in shaping adipose heterogeneity and treating metabolic disorders.
Adipose Tissue/pathology , Adult Stem Cells/metabolism , Apoptosis/drug effects , Cytokines/metabolism , Metabolic Syndrome/metabolism , Tumor Necrosis Factor-alpha/pharmacology , Adipose Tissue/metabolism , Adult Stem Cells/drug effects , Adult Stem Cells/physiology , Aged , Apoptosis/genetics , Cell Hypoxia/physiology , Cells, Cultured , Female , Humans , Male , Metabolic Syndrome/etiology , Metabolic Syndrome/pathology , Middle Aged , Paracrine Communication/drug effects , Paracrine Communication/genetics , Paracrine Communication/physiology , RNA-Seq , Risk Factors , Single-Cell Analysis/methods
Background: The gut microbiome plays an important role in the lipid metabolism. Antibiotic treatment causes changes in the intestinal microbiota. Our objective was to explore the relationship between changes in the intestinal microbiota and the level of plasma high density lipoprotein cholesterol (HDL) and low density lipoprotein cholesterol (LDL). Methods: Prospective case-control study with Helicobacter pylori-positive patients undergoing eradication therapy with omeprazole, clarithromycin, and amoxicillin. Stool and blood samples were obtained from 20 controls (H. pylori negative) and 40 patients before and 2 months after antibiotic treatment. Gut microbiota was determined through 16S rRNA amplicon sequencing (Illumina MiSeq). Results: Eradication treatment for H. pylori increased the HDL levels, and caused changes in gut microbiota profiles. An unfavorable lipid profiles (high LDL and low HDL levels) was associated with a low microbial richness and an increase of the Bacteroidetes phylum. Prevotella copri, Lachonobacterium, and Delsufovibrio were positively associated with HDL while Rikenellaceae was negatively associated with HDL after completing antibiotic treatment. Conclusions: Helicobacter pylori eradication treatment could improve lipid metabolism in relation with an increase in the HDL. Changes in the abundance of specific bacteria, such as P. copri, Lachonobacterium, Delsufovibrio, and Rikenellaceae could be associated with change in the plasma HDL levels.
Obesity and metabolic syndrome are among the most prevalent health problems in developed countries. The impairment of adipose tissue (AT) function is partially responsible for the aetiology of these conditions. Epigenetics refers to several processes that add modifications to either the DNA or chromatin architectural proteins (histones). These processes can regulate gene expression, chromatin compaction and DNA repair. Epigenetics includes mechanisms by which the cell can adapt the cellular response to the environmental conditions. Here, we review the role of epigenetics in the onset of obesity and related metabolic disorders, with special focus on AT. We highlight the importance of nutrients and lifestyle in the regulation of the epigenetic mechanisms and how they can impact on AT plasticity and function in obesity and metabolic diseases. Thus, the epigenetic landscape emerges as a fine-tune regulator of the cellular responses according to the energetic, metabolic and physiological conditions of the cell. Alterations in metabolic pathways deregulated during obesity and metabolic syndrome could in part explain the disturbances in the epigenetic marks of the AT in these disorders. The understanding of how this epigenetic deregulation may affect AT biology and function could lead to new therapeutic approaches based on epigenetic strategies.
Adipose Tissue, White/metabolism , Epigenesis, Genetic , Metabolic Syndrome , Obesity , Humans , Metabolic Syndrome/genetics , Obesity/genetics
Despite the fact that circulating levels of proprotein convertase subtilisin/kexin type 9 (PCSK9) remain unchanged after fat load in healthy lean individuals, PCSK9 has been suggested to have a role in postprandial lipemia regulation in obese individuals. On the other hand, intestinal permeability and endotoxemia have been observed to increase more in obese individuals than in non-obese individuals after a lipid load. This study aimed to analyze the relationship between PCSK9, intestinal permeability, and endotoxemia after a high fat load in obese individuals. We included 39 individuals with morbid obesity. Serum PCSK9 levels, intestinal permeability marker (zonulin), endotoxemia markers (LPS and LBP), and lipid parameters were measured before and after 3 h of fat load. A significant rise in triglycerides, apolipoprotein A1, zonulin, LPS, and LBP, and a significant decline in PCSK9, were observed after a lipid load. Linear regression analysis showed that low-density lipoprotein cholesterol (LDL-C) was independently related to PCSK9 at baseline, whereas both zonulin and LDL-C were independently related to PCSK9 levels after fat load. A relationship between zonulin and PCSK9 levels after fat load in individuals with morbid obesity may exist.
Haptoglobins/metabolism , Obesity/blood , Proprotein Convertase 9/blood , Protein Precursors/metabolism , Adult , Diet, High-Fat , Female , Humans , Linear Models , Male
Multifunctional biocompatible materials have evoked considerable interest in the field of medical applications. Here we report the thermal decomposition preparation of homogeneous fluorescent-magnetic particles with a composite structure containing CoFe2O4 nanoparticles as nucleation seeds for fluorescent Gd2-xO3:Eux. The composite exhibited a wide range of fluorescence transitions in the whole visible spectrum, displaying 18 different emission peaks when excited at a 250 nm wavelength. Moreover, at low temperature the peaks of the composite were wider than the peaks of the fluorescent material, which may be attributed to a set of new energy levels due to a combination of Stark splitting with the magnetic field of CoFe2O4. Because this material is intended to be used for biomedical applications, the potential toxicity of the composite was tested using an invertebrate hemocyte cell model. The cells showed slight morphological and biochemical changes upon exposure to the composite; however, there was no increase in cell death at concentrations of up to 40 ppm. In addition, the material could be tracked by its fluorescence inside the cells, when excited at a more bio-friendly and less energetic wavelength of 405 nm. Furthermore, MRI showed T1 and T2 dual contrast with relaxivity values in the range of most reported materials.
BACKGROUND: Recent works have reported that bariatric surgery has remarkable effects on the metabolome, which might be potentially associated to the metabolic improvement of this procedure in patients with obesity. Serum polyamines, metabolites derived from amino acid metabolism, have been recently related to the metabolic status in obese individuals. However, the impact of bariatric surgery on the circulating levels of polyamines remains elusive. OBJECTIVE: To evaluate the effect of bariatric surgery on serum polyamine levels and to evaluate the association of changes in these molecules with metabolic improvement in patients with morbid obesity. SETTING: Virgen de la Victoria University Hospital, Malaga, Spain. METHODS: This study included 32 morbidly obese patients (weight index ≥40 kg/m2) with metabolic syndrome, who underwent sleeve gastrectomy. Serum levels of polyamines (putrescine, spermidine, and spermine), acetylpolyamines, and polyamine-related amino acids (arginine and ornithine) were assessed at baseline and 6 months after bariatric surgery, and were analyzed in an ultraperformance liquid chromatography-mass spectrometry platform. RESULTS: Our metabolomic analysis revealed a significant rise in several metabolites related to the polyamine metabolism, such as putrescine and acetyl derivatives of spermidine and spermine in serum samples from morbidly obese patients after bariatric surgery. Changes in serum levels of both putrescine and acetylputrescine were associated to the resolution of metabolic syndrome after surgery. CONCLUSION: Our study indicates that bariatric surgery affects the serum polyamine pattern and the resolution of metabolic syndrome after bariatric surgery is associated to specific changes in the serum polyamine metabolome.
Bariatric Surgery , Metabolic Syndrome , Obesity, Morbid , Humans , Metabolome , Obesity, Morbid/surgery , Polyamines , Spain
BACKGROUND: Monoamine oxidase (MAO) activity has been traditionally implicated in blood pressure through its effects on biogenic amine levels such as catecholamines, serotonin, and dopamine. Nowadays, this role is considered relegated to side-effects such as orthostatic hypotension and/or hypertensive crisis derived from MAO-inhibitory treatments in patients with psychiatric disease. METHODS: In the present work we have found an association between a polymorphic variant of MAOB gene and arterial hypertension in obese hypogonadic patients. The study cases comprised a series of 219 nondiabetic males with a body mass index ≥30 kg/m2 and aged <45 years. Hypogonadism was defined as subnormal testosterone concentrations, when free testosterone values ranged <65 pg/ml. RESULTS: MAOB rs3027452-A allele carriers were significantly over-represented among hypertensive (HT) patients (25.49%) in comparison to either the non-HT patients (10%, OR = 3.079 CI95 [1.364-6.952], p = .005, Chi-square test) and the control population series of nonobese nor hypogonadic males (also 10%, p = .003 Chi-square test). Upon adjusted, an independent association was shown with the hypogonadic group with hypertension when compared with nonhypertensive hypogonadics (Beta = 3.653, p = .005). When quantitative analysis was performed, hypertensive patients harboring rs3027452-A allele showed higher systolic blood pressure values (p = .038, Mann-Whitney U-test) as well as an increased Systolic-Diastolic range despite following HT treatment (∆mmHg 54 vs. 48 for rs3027452-A and rs3027452-G respectively, p-value .019, Mann-Whitney U-test). Previous studies on MAOB revealed that rs3027452-A allele has been correlated to a lower activity of the enzyme, what gives a functional evidence over our observation. CONCLUSION: If this result could be extrapolated to other hypertensive patient groups, it would implicate a review of the markers and therapeutic targets on human hypertension.
Eunuchism/complications , Hypertension/genetics , Monoamine Oxidase/genetics , Polymorphism, Single Nucleotide , Adult , Blood Pressure , Body Mass Index , Humans , Hypertension/epidemiology , Male , Testosterone/blood
BACKGROUND: Obesity is associated with several comorbid disorders, ranging from cardiovascular diseases to insulin resistance. In this context, visceral adipose tissue (VAT) seems to have a close connection with insulin resistance. In our study, we hypothesized that the expression profile of key adipogenic genes, such as proliferator-activated receptor γ type 2 (PPAR-γ2), CCAAT/enhancer-binding protein type α (C/EBP-α), and forkhead box protein class O type 1 (FOXO1) in VAT should shed light on their association with obesity-related insulin resistance. METHODS: To test this idea, we studied the expression profile of C/EBP-α, FOXO1 and PPAR-γ2 in VAT from non-obese individuals, and low insulin (LIR-MO) and high insulin morbidly obese (HIR-MO) subjects, through a combination of RT-qPCR, co-immunoprecipitation, ELISA, Western blot analysis and EMSA assays. RESULTS: Our results show that C/EBP-α and PPAR-γ2 were down-expressed in HIR-MO individuals, while FOXO1 was overexpressed. In addition, the PPAR-γ2-RXR-α heterodimer showed weak activity and bound weakly to the putative IGFBP-2-PPRE promoter sequence in VAT from HIR-MO subjects when compared with LIR-MO individuals. CONCLUSIONS: These results show that PPAR-γ2, C/EBP-α, FOXO1 and IGFBP-2 have a close relationship with insulin resistance in VAT of morbidly obese individuals.
CCAAT-Enhancer-Binding Protein-alpha/genetics , Forkhead Box Protein O1/genetics , Insulin Resistance , Obesity, Morbid/genetics , PPAR gamma/genetics , Adult , Aged , CCAAT-Enhancer-Binding Protein-alpha/metabolism , Female , Forkhead Box Protein O1/metabolism , Humans , Insulin-Like Growth Factor Binding Protein 2/genetics , Insulin-Like Growth Factor Binding Protein 2/metabolism , Male , Middle Aged , Obesity, Morbid/metabolism , PPAR gamma/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism
INTRODUCTION: Obesity has been associated with increased risk of presenting hypogonadism. Free testosterone (FT) is the fraction of testosterone that carries out the biological function of testosterone, and is determined from total testosterone (TT) and sex-hormone binding globulin (SHBG) levels. We aimed to study the SHBG polymorphism rs1799941 in a cohort of young non-diabetic obese males to unravel the possible implication of this polymorphism in obesity-related hypogonadism. METHODOLOGY: 212 young (<45 years) non-diabetic obese (BMI ≥ 30 kg/m2) males participated in this study. Subjects were classified according to TT and FT levels in: Eugonadal (n = 55, TT > 3.5 ng/mL and FT ≥ 70 pg/mL; EuG), normal FT hypogonadism (n = 40, TT < 3.5 and FT ≥ 70 pg/mL; normal FT HG) and hypogonadism (n = 117, TT < 3.5 ng/mL and TL < 70 pg/mL; HG). The SHBG rs1799941 polymorphism (GG/GA/AA) was analyzed using the Taqman Open Array (Applied biosystem). RESULTS: The rs1799941 frequencies were different among the groups. Higher proportion of the allele (A) was found in HG, compared to EuG and normal FT HG. Among the genotypes, the rare homozygous (AA) were found in the normal FT HG group and higher levels of serum SHBG and lower of FT were observed. The presence of the allele A was related (according to lineal regression models) to an increased of SHBG levels ((GA) ß = 3.28; (AA) ß = 12.45) and a decreased of FT levels ((GA) ß = -9.19; (AA) ß = -18.52). The presence of the allele (A) increased the risk of presenting HG compared to normal FT HG (OR = 2.54). CONCLUSIONS: The rs1799941 of the SHBG gene can partially determine the presence of obesity-related hypogonadism in young non-diabetic males and whether these subjects have normal FT HG.
