Development of a genetic risk score for obesity predisposition evaluation.

Obesity is a major public health issue resulting from an interaction between genetic and environmental factors. Genetic risk scores (GRSs) are useful to summarize the effects of many genetic variants on obesity risk. In this study, we aimed to assess the association of previously well-studied genetic variants with obesity and develop a genetic risk score to anticipate the risk of obesity development in the Iranian population. Among 968 participants, 599 (61.88%) were obese, and 369 (38.12%) were considered control samples. After genotyping, an initial screening of 16 variants associated with body mass index (BMI) was performed utilizing a general linear model (p < 0.25), and seven genetic variants were selected. The association of these variants with obesity was examined using a multivariate logistic regression model (p < 0.05), and finally, five variants were found to be significantly associated with obesity. Two gene score models (weighted and unweighted), including these five loci, were constructed. To compare the discriminative power of the models, the area under the curve was calculated using tenfold internal cross-validation. Among the studied variants, ADRB3 rs4994, FTO rs9939609, ADRB2 rs1042714, IL6 rs1800795, and MTHFR rs1801133 polymorphisms were significantly associated with obesity in the Iranian population. Both of the constructed models were significantly associated with BMI (p < 0.05) and the area under the mean curve of the weighted GRS and unweighted GRS were 70.22% ± 0.05 and 70.19% ± 0.05, respectively. Both GRSs proved to predict obesity and could potentially be utilized as genetic tools to assess the obesity predisposition in the Iranian population. Also, among the studied variants, ADRB3 rs4994 and FTO rs9939609 polymorphisms have the highest impacts on the risk of obesity.

Differential S-palmitoylation of the human and rodent ß3-adrenergic receptors.

With few reported exceptions, G protein-coupled receptors (GPCRs) are modified by Cys palmitoylation (S-palmitoylation). In multiple GPCRs, S-palmitoylation targets a canonical site within the C-terminal cytoplasmic tail adjacent to the C terminus of the seventh transmembrane domain, but modification of additional sites is exemplified by the ß-adrenergic receptors (ßARs). The ß1AR is S-palmitoylated at a second, more distal site within the C-terminal tail, and the ß2AR is modified at a second site within the third intracellular loop, neither of which is conserved in other ßAR isoforms. The functional roles of S-palmitoylation of disparate sites are incompletely characterized for any GPCR family. Here, we describe S-palmitoylation of the ß3AR. We compared mouse and human ß3ARs and found that both were S-palmitoylated at the canonical site within the C-terminal tail, Cys-358 and Cys-361/363 in mouse and human ß3ARs, respectively. Surprisingly, the human ß3AR was S-palmitoylated at two additional sites, Cys-153 and Cys-292 within the second and third intracellular loops, respectively. Cys-153 is apparently unique to the human ß3AR, and Cys-292 is conserved primarily in primates. Mutational substitution of C-tail Cys in human but not mouse ß3ARs resulted in diminished ligand-induced cAMP production. Substitution of Cys-153, Cys-292, or Cys-361/363 within the human ß3AR diminished membrane-receptor abundance, but only Cys-361/363 substitution diminished membrane-receptor half-life. Thus, S-palmitoylation of different sites differentially regulates the human ß3AR, and differential S-palmitoylation distinguishes human and rodent ß3ARs, potentially contributing to species-specific differences in the clinical efficacy of ß3AR-directed pharmacological approaches to disease.

ADRB3 expression in tumor cells is a poor prognostic factor and promotes proliferation in non-small cell lung carcinoma.

The cross-talk between cancer cells and monocyte-derived alveolar macrophages (Mo-AMs) promotes non-small cell lung carcinoma (NSCLC) progression. In this study, we report that both cancer cells and Mo-AMs robustly express beta 3-adrenergic receptor (ADRB3) in NSCLC. ADRB3 supports lung cancer cells proliferation and promotes chronic inflammation. Genetic and pharmacologic inhibition of ADRB3 reverses tumor growth and inflammation in mouse. Furthermore, we demonstrate that M5D1, a novel anti-ADRB3 monoclonal antibody, inhibits human lung cancer cells proliferation and inflammation via affecting the intracellular mTOR pathway and activating p53. In NSCLC patients, we confirmed that upregulation of ADRB3 expression correlates with tumor progression and poor prognosis. Altogether, these results shed light on the role of ADRB3 in NSCLC and suggest that M5D1 could become powerful antitumor weapons.

The Trp64Arg polymorphism in ß3 adrenergic receptor (ADRB3) gene is associated with adipokines and plasma lipids: a systematic review, meta-analysis, and meta-regression.

BACKGROUND: Recently, some studies claim that adipokines may modulate plasma lipids. More interestingly, the ADRB3 Trp64Arg polymorphism may regulate adipokines and play an essential role in lipids metabolism. This study aims to clarify the associations of ADRB3 Trp64Arg polymorphism with plasma adipokines and lipid levels. METHODS: Twenty-two studies (5527 subjects) and 121 studies (54,059 subjects) were respectively identified for the association analyses of adipokines and lipids. Standardized mean difference (SMD) and 95% confidence interval (CI) were used to estimate the strength of the Trp64Arg variant in adipokines and plasma lipids. All results were recalculated after eliminating the studies with heterogeneity. RESULTS: The carriers of the C allele (Arg at 64th position was encoded by the C allele) had higher levels of leptin and lower levels of adiponectin than the non-carriers. The carriers of the C allele had higher levels of triglycerides (TG), total cholesterol (TC), and lower levels of high-density lipoprotein cholesterol (HDL-C) than the non-carriers. Subgroup analysis certified an ethnicity (Asians), disease status (obesity), and gender (females) specific association. Sensitivity analysis indicated that the analysis results were robust and stable. Meta-regression indicated that obesity was related to adiponectin. CONCLUSIONS: The C allele carriers of Trp64Arg polymorphism had a slight but significant influence on lipid levels, and the remarkable effects specific existed in obese Asian women. The associations of Trp64Arg polymorphism with dyslipidemia may partly be mediated by the effect of this polymorphism on adipokines. The association of Trp64Arg polymorphism with obesity may partly be mediated by the effect of this polymorphism on adipokines. The C allele carriers had abnormal levels of adipokines and lipids, and it indicated that the Trp64Arg polymorphism might represent a genetic risk factor for coronary artery disease (CAD).

Role of ß-3 adrenergic receptor polymorphism in overactive bladder.

AIMS: Women with overactive bladder (OAB) have a higher frequency of a single-nucleotide polymorphism (SNP) at codon 64 of the ß-3 adrenergic receptor gene (ADRB3). Since the SNP results in an amino acid substitution that could theoretically alter receptor protein function, we hypothesized that those with the SNP would display greater OAB symptom severity. Therefore we aimed to compare OAB severity between women with this SNP and women with the wild type genotype. METHODS: A retrospective cohort study was performed in women with bothersome OAB from two academic institutions. Banked blood samples were tested for the codon 64 SNP. Women were divided into two groups based on genotype: wild-type (WT) and heterozygous (HZ). We compared mean OAB Symptom Severity questionnaire (OAB-q) scores between groups using t tests. Linear regression was performed to control for potential confounders. RESULTS: Of the 303 women with OAB, 254 (83.8%) had the WT genotype, and 49 (16.2%) the HZ genotype. There were no homozygous women for the rare allele. The majority were Caucasian (86%) and non-Hispanic (97%). There were no significant differences in mean OAB-q symptom severity scores (WT 21.2 ± 7 vs HZ 22.0 ± 6.6; P = 0.49) and quality of life scores (WT 39.6 ± 15.5 vs HZ 39.1 ± 16.6; P = 0.83) between groups. These remained nonsignificant in a linear regression model. CONCLUSIONS: In a predominantly non-Hispanic, Caucasian population of women with bothersome OAB, symptom severity was not related to ADRB3 codon 64 SNP genotype.

Methylation profile of the ADRB3 gene and its association with lipid profile and nutritional status in adults.

BACKGROUND: Defects in DNA methylation have been shown to be associated with metabolic diseases such as obesity, dyslipidemia, and hypercholesterolemia. To analyze the methylation profile of the ADRB3 gene and correlate it with lipid profile, lipid intake, and oxidative stress based on malondialdehyde (MDA) and total antioxidant capacity (TAC), homocysteine and folic acid levels, nutritional status, lifestyle, and socioeconomic variables in an adult population. A cross-sectional epidemiological study representative of the East and West regions of the municipality of João Pessoa, Paraíba state, Brazil, enrolled 265 adults of both genders. Demographic, lifestyle, and socioeconomic questionnaires and a 24-h recall questionnaire were applied by trained interviewers' home. Nutritional and biochemical evaluation (DNA methylation, lipid profile, MDA, TAC, homocysteine and folic acid levels) was performed. RESULTS: DNA hypermethylation of the ADRB3 gene, analyzed in leukocytes, was present in 50% of subjects and was associated with a higher risk of being overweight (OR 3.28; p = 0.008) or obese (OR 3.06; p = 0.017), a higher waist-hip ratio in males (OR 1.17; p = 0.000), greater intake of trans fats (OR 1.94; p = 0.032), higher LDL (OR 2.64; p = 0.003) and triglycerides (OR 1.81; p = 0.031), and higher folic acid levels (OR 1.85; p = 0.022). CONCLUSIONS: These results suggest that epigenetic changes in the ADRB3 gene locus may explain the development of obesity and non-communicable diseases associated with trans-fat intake, altered lipid profile, and elevated folic acid. Because of its persistence, DNA methylation may have an impact in adults, in association with the development of non-communicable diseases. This study is the first population-based study of the ADRB3 gene, and the data further support evaluation of ADRB3 DNA methylation as an effective biomarker.

Decrease of the DNA methylation levels of the ADRB3 gene in leukocytes is related with serum folate in eutrophic adults.

BACKGROUND: DNA methylation has been evidenced as a potential epigenetic mechanism related to various candidate genes to development of obesity. Therefore, the objective of this study was to evaluate the DNA methylation levels of the ADRB3 gene by body mass index (BMI) in a representative adult population, besides characterizing this population as to the lipid profile, oxidative stress and food intake. METHODS: This was a cross-sectional population-based study, involving 262 adults aged 20-59 years, of both genders, representative of the East and West regions of the municipality of João Pessoa, Paraíba state, Brazil, in that were evaluated lifestyle variables and performed nutritional, biochemical evaluation and DNA methylation levels of the ADRB3 gene using high resolution melting method. The relationship between the study variables was performed using analyses of variance and multiple regression models. All results were obtained using the software R, 3.3.2. RESULTS: From the stratification of categories BMI, was observed a difference in the average variables values of age, waist-to-height ratio, waist-to-hip ratio, waist circumference, triglycerides and intake of trans fat, which occurred more frequently between the categories "eutrophic" and "obesity". From the multiple regression analysis in the group of eutrophic adults, it was observed a negative relationship between methylation levels of the ADRB3 gene with serum levels of folic acid. However, no significant relation was observed among lipid profile, oxidative stress and food intake in individuals distributed in the three categories of BMI. CONCLUSIONS: A negative relationship was demonstrated between methylation levels of the ADRB3 gene in eutrophic adults individuals with serum levels of folic acid, as well as with the independent gender of BMI, however, was not observed relation with lipid profile, oxidative stress and variables of food intake. Regarding the absence of relationship with methylation levels of the ADRB3 gene in the categories of overweight, mild and moderate obesity, the answer probably lies in the insufficient amount of body fat to initiate inflammatory processes and oxidative stress with a direct impact on methylation levels, what is differently is found most of the times in exacerbated levels in severe obesity.

Individual Responsiveness to Exercise-Induced Fat Loss and Improvement of Metabolic Profile in Young Women is Associated with Polymorphisms of Adrenergic Receptor Genes.

The effectiveness of physical exercise on fat loss and improvement of aerobic capacity varies considerably between individuals. A strong linkage exists between common allelic variants of the adrenergic receptor genes and weight gain, as well as changes in body composition. Therefore we aimed to check if body composition and metabolic variables were modulated by the ADRB2 (Gly16Arg and Glu27Gln), ADRB3 (Trp64Arg) and ADRA2A (rs553668 G/A) gene polymorphisms in 163 Polish sedentary women (age 19-24; body mass index (BMI) 21.7 ± 0.2 kg·m-2) involved in a 12-week aerobic training program. Only 74.8% of participants lost fat mass. On average, participants lost 5.8 (10.4)% of their relative fat mass with training (range: +28.3 to -63.6%). The improvement of VO2max was significantly greater in women who could lose their fat mass compared to women who were unsuccessful in fat loss (4.5 (5.6)% vs. 1.5 (3.8)%; p = 0.0045). The carriers of a low number (0-3) of obesity-related risk alleles (ADRB2 Gly16, ADRB2 Glu27, ADRA2A rs553668 G) were more successful in fat mass loss compared to the carriers of a high number (5-6) of risk alleles (7.7 (9.8) vs 4.0 (9.4)%, p = 0.0362). The presented results support the assumption that variation within adrenergic receptor genes contributes to interindividual changes of body composition in response to physical exercise.

Association analysis of the beta-3 adrenergic receptor Trp64Arg (rs4994) polymorphism with urate and gout.

The Arg64 allele of variant rs4994 (Trp64Arg) in the ß3-adrenergic receptor gene has been associated with increased serum urate and risk of gout. Our objective was to investigate the relationship of rs4994 with serum urate and gout in New Zealand European, Maori and Pacific subjects. A total of 1730 clinically ascertained gout cases and 2145 controls were genotyped for rs4994 by Taqman(®). Maori and Pacific subjects were subdivided into Eastern Polynesian (EP) and Western Polynesian (WP) sample sets. Publicly available genotype data from the Atherosclerosis Risk in Communities Study and the Framingham Heart Study were utilized for serum urate association analysis. Multivariate logistic and linear regression adjusted for potential confounders was carried out using R version 2.15.2. No significant association of the minor Arg64 (G) allele of rs4994 with gout was found in the combined Polynesian cohorts (OR = 0.98, P = 0.88), although there was evidence, after adjustment for renal disease, for association in both the WP (OR = 0.53, P = 0.03) and the lower Polynesian ancestry EP sample sets (OR = 1.86, P = 0.05). There was no evidence for association with gout in the European sample set (OR = 1.11, P = 0.57). However, the Arg64 allele was positively associated with urate in the WP data set (ß = 0.036, P = 0.004, P Corrected = 0.032). Association of the Arg64 variant with increased urate in the WP sample set was consistent with the previous literature, although the protective effect of this variant with gout in WP was inconsistent. This association provides an etiological link between metabolic syndrome components and urate homeostasis.

[The study of energy balance in individuals with the Trp64Arg polymorphism of the ß3-adrenoreceptor gene].

The study involved 104 people living in the Moscow region, including 18 men and 86 women aged 18 to 67 years. Genotyping of rs4994 ADRB3 polymorphisms was performed using allele-specific amplification, with result detection in real time and using TaqMan-probes complementary to polymorphic DNA regions. The frequency of the mutant allele in individuals was 8.0%, while the Trp64Trp genotype was detected in 84.0% of cases, Trp64Ar - in 16.0%, AA - in 19.0%. Compared with men with genotype Trp64Trp, the men with the Trp64Ar polymorphisms (rs4994) of ADRB3 gene had significantly lower energy expenditure at rest value, calculated per kg of body muscle mass that was associated with higher fat mass, levels of blood serum leptin and LDL cholesterol. The data obtained suggested that leptin could be a possible intermediary contributing to the association between the rs4994 polymorphism of ADRB3 gene and energy disbalance.

The Role of ß3-Adrenergic Receptors in Cold-Induced Beige Adipocyte Production in Pigs.

After exposure to cold stress, animals enhance the production of beige adipocytes and expedite thermogenesis, leading to improved metabolic health. Although brown adipose tissue in rodents is primarily induced by ß3-adrenergic receptor (ADRB3) stimulation, the activation of major ß-adrenergic receptors (ADRBs) in pigs has been a topic of debate. To address this, we developed overexpression vectors for ADRB1, ADRB2, and ADRB3 and silenced the expression of these receptors to observe their effects on the adipogenic differentiation stages of porcine preadipocytes. Our investigation revealed that cold stress triggers the transformation of subcutaneous white adipose tissue to beige adipose tissue in pigs by modulating adrenergic receptor levels. Meanwhile, we found that ADRB3 promotes the transformation of white adipocytes into beige adipocytes. Notably, ADRB3 enhances the expression of beige adipose tissue marker genes, consequently influencing cellular respiration and metabolism by regulating lipolysis and mitochondrial expression. Therefore, ADRB3 may serve as a pivotal gene in animal husbandry and contribute to the improvement of cold intolerance in piglets.

Stress-inducible IL-6 is regulated by KLF7 in brown adipocytes.

Stress-inducible interleukin 6 (IL-6) is generated in brown adipocytes via beta-3 adrenergic receptor (ADRB3) signaling, which is necessary in stress hyperglycemia, the kind of metabolic adaptation enabling "fight or flight" response by means of liver gluconeogenesis. Nevertheless, the mechanism of ADRB3 signaling mediates IL-6 in brown adipocytes remains unclear. As a result, it is critical to understand how brown adipocytes produce IL-6 via ADRB3 signaling. We found that the ADRB3 agonist and cold stimulation promoted the expression of KLF7 and IL-6 in brown adipocytes of mice. In parallel to these results in vivo, treatment with ADRB3 agonist promoted the expression of KLF7 and the release of IL-6 in primary brown adipocytes of mice. Notably, we discovered that KLF7 positively controls the expression of IL-6 and downregulated KLF7 largely blunted ADRB3 agonist induced IL-6 expressions in brown adipocytes. Our findings suggest that KLF7 is required for the generation of IL-6 when ADRB3 signaling is activated in brown adipocytes.

Effects of the Trp64Arg Polymorphism in the ADRB3 Gene on Body Composition, Cardiorespiratory Fitness, and Physical Activity in Healthy Adults.

The ADRB3 gene plays a role in energy expenditure by participating in lipolysis, which affects body composition and performance. The ADRB3 rs4994 polymorphism has been studied in groups of athletes, overweight individuals, and obese and diabetic patients, but it has not been studied in young and healthy adults so far. In the present study, we examined the association of ADRB3 rs4994 polymorphism with body composition, somatotype, cardiorespiratory fitness and physical activity in young, healthy adults (N = 304). All subjects had anthropometric measurements, and somatotypes were assessed using the Heath-Carter method. In addition, cardiorespiratory fitness and physical activity levels were assessed. Genotyping for the ADRB3 gene was performed using a PCR-RFLP method. In the male group, body components were associated with the Trp64Trp genotype (waist circumference (p = 0.035), hip circumference (p = 0.029), BF (%) (p = 0.008), and BF (kg) (p = 0.010), BMI (p = 0.005), WHtR (p = 0.021), and BAI (p = 0.006)). In addition, we observed that the Trp64Trp genotype was associated with somatotype components (p = 0.013). In contrast, the Arg allele was associated with the ectomorphic components (0.006). We also observed a positive impact of the Trp64Trp genotype with maximal oxygen uptake (p= 0.023) and oxygen pulse (p = 0.024). We observed a negative relationship of the Trp64Trp genotype in the female group with reported moderate-intensity exercise (p = 0.036). In conclusion, we found an association of the Trp64 allele with anthropometric traits, somatotype and parameters describing physical performance in the male group. In the female subpopulation, we only found an effect of the polymorphism Trp64Arg on the level of physical activity for moderate-intensity exercise.

Association of an ADRB3 Variant with Coronary Artery Disease Within the Chinese Han Population: Construction of a Predictive Nomogram Model.

Objective: Coronary artery disease (CAD) is a the most common type of heart disease, and is associated with the highest mortality rate. The role of the ß3-adrenergic receptor gene (ADRB3) in energy homeostasis and lipolysis suggests that it may be associated with obesity, insulin resistance, diabetes, and hypertension. Herein, we sought to examine the relationship between CAD and variants of the ADRB3 gene in individuals with Han and Uygur ethnicities in China. Methods: All 1022 participants were genotyped for two ADRB3 single nucleotide polymorphisms (SNPs; rs1892818 and rs9693898) using real-time polymerase chain reaction (TaqMan). Uygur (259 CAD patients, 161 control group) and Han (308 CAD patients, 294 control group) were included in two case-control studies. We subsequently developed a predictive model using ADRB3 genetic variation and clinical variables to predict risk of CAD. Results: The rs1892818 CT genotype (8.5% vs 3.9%, p = 0.019) and T allele (4.3% vs 1.9%, p = 0.021) were more frequently detected in the control subjects compared to CAD patients of the Han population but not in the Uygur population. The rs9693898 was not associated with CAD in either ethnic population. Logistic regression analysis further demonstrated that carriers of the rs1892818 CT genotype had a lower risk of CAD than did those with the CC genotype (CT vs CC, p = 0.044, odds ratio [OR] = 0.441, 95% confidence interval [CI]: 0.199-0.976). Using this data, we constructed a predictive nomogram model for CAD with an area under the curve (95% CI) of 0.722 (0.682, 0.761). Conclusions: Our results suggest that rs1892818 is associated with CAD in the Han population and that the CT genotype of rs1892818 may serve as a protective factor for CAD in Han individuals. The proposed nomograms can be used for the prediction of CAD in this population.

Dietary polyphenols and their relationship to the modulation of non-communicable chronic diseases and epigenetic mechanisms: A mini-review.

Chronic Non-Communicable Diseases (NCDs) have been considered a global health problem, characterized as diseases of multiple factors, which are developed throughout life, and regardless of genetics as a risk factor of important relevance, the increase in mortality attributed to the disease to environmental factors and the lifestyle one leads. Although the reactive species (ROS/RNS) are necessary for several physiological processes, their overproduction is directly related to the pathogenesis and aggravation of NCDs. In contrast, dietary polyphenols have been widely associated with minimizing oxidative stress and inflammation. In addition to their antioxidant power, polyphenols have also drawn attention for being able to modulate both gene expression and modify epigenetic alterations, suggesting an essential involvement in the prevention and/or development of some pathologies. Therefore, this review briefly explained the mechanisms in the development of some NCDs, followed by a summary of some evidence related to the interaction of polyphenols in oxidative stress, as well as the modulation of epigenetic mechanisms involved in the management of NCDs.

Can study of the ADRB3 gene help improve weight loss programs in obese individuals? / ¿Puede el estudio del gen ADRB3 ayudar a mejorar los programas de pérdida de peso en individuos obesos?

INTRODUCTION: Obesity is a chronic disease of multifactorial origin characterized by excess weight and excess fat accumulation, and whose etiology includes intrinsic (genetic, physiological, and metabolic) and extrinsic (social and cultural) factors. Fat accumulation is caused by a prolonged imbalance in the energy balance influenced, among other factors, by adaptive thermogenesis, which is triggered by cold environmental conditions, or by hypercaloric intake. Thermogenesis is regulated by the sympathetic nervous system and occurs in the muscle and brown adipose tissue. There are adrenergic receptors in brown adipose tissue, including the beta-3 adrenergic receptor (ADRB3), the main receptor for the regulation of thermogenesis. The presence in heterozygosis of an SNP-type polymorphism in the ADRB3 gene (Trp64Arg; rs4994) is associated with a lower lipolytic activity, a predisposition to obesity, and resistance to weight loss. The objective of this study was to analyze through a systematic review the weight loss program most appropriate for carriers. METHODS: A retrospective study of published papers on rs4994 polymorphism in the SNP and PubMed databases was conducted. RESULTS: Most published studies suggest the presence of obesity and resistance to weight loss in carriers, and report significant improvements in anthropometric parameters when patients receive fat-rich hypocaloric diets. CONCLUSIONS: Based on these conclusions, specific nutritional and physical exercise guidelines are proposed for individuals carrying the Trp64Arg allele.

The crosstalk of HDAC3, microRNA-18a and ADRB3 in the progression of heart failure.

BACKGROUND: Heart failure (HF) is a clinical syndrome characterized by left ventricular dysfunction or elevated intracardiac pressures. Research supports that microRNAs (miRs) participate in HF by regulating  targeted genes. Hence, the current study set out to study the role of HDAC3-medaited miR-18a in HF by targeting ADRB3. METHODS: Firstly, HF mouse models were established by ligation of the left coronary artery at the lower edge of the left atrial appendage, and HF cell models were generated in the cardiomyocytes, followed by ectopic expression and silencing experiments. Numerous parameters including left ventricular posterior wall dimension (LVPWD), interventricular septal dimension (IVSD), left ventricular end diastolic diameter (LVEDD), left ventricular end systolic diameter (LVESD), left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LEVDP), heart rate (HR), left ventricular pressure rise rate (+ dp/dt) and left ventricular pressure drop rate (-dp/dt) were measured in the mice. In addition, apoptosis in the mice was detected by means of TUNEL staining, while RT-qPCR and Western blot analysis were performed to detect miR-18a, HDAC3, ADRB3, cMyb, MMP-9, Collagen 1 and TGF-ß1 expression patterns. Dual luciferase reporter assay validated the targeting relationship between ADRB3 and miR-18a. Cardiomyocyte apoptosis was determined by means of flow cytometry. RESULTS: HDAC3 and ADRB3 were up-regulated and miR-18a was down-regulated in HF mice and cardiomyocytes. In addition, HDAC3 could reduce the miR-18a expression, and ADRB3 was negatively-targeted by miR-18a. After down-regulation of HDAC3 or ADRB3 or over-expression of miR-18a, IVSD, LVEDD, LVESD and LEVDP were found to be decreased but LVPWD, LVEF, LVFS, LVSP, + dp/dt, and -dp/dt were all increased in the HF mice, whereas fibrosis, hypertrophy and apoptosis of HF cardiomyocytes were declined. CONCLUSION: Collectively, our findings indicate that HDAC3 silencing confers protection against HF by inhibiting miR-18a-targeted ADRB3.

Association of FTO, ABCA1, ADRB3, and PPARG variants with obesity, type 2 diabetes, and metabolic syndrome in a Northwest Mexican adult population.

AIM: To identify associations among allelic variants of the genes FTO, ABCA1, ADRB3, and PPARG with anthropometric and biochemical traits, metabolic diseases (obesity, T2D or metabolic syndrome) in an adult population from Northwest Mexico. METHODS: Blood samples were collected from 846 subjects including 266 normal weight subjects, 285 with obesity, and 295 with T2D. Of the 846 persons in the study, 365 presented metabolic syndrome diagnostic criteria. Anthropometric and biochemical traits were recorded and 4 single nucleotide polymorphisms (SNPs): FTO rs9939609 A-allele, ABCA1 rs9282541 A-allele, ADRB3 rs4994 G-allele, and PPARG rs1801282 G-allele were genotyped by real-time PCR. RESULTS: FTO rs9939609 A-allele was significantly associated with obesity (p: 8.3 × 10-4), and metabolic syndrome (p: 0.001), but no individual SNPs were significantly associated with T2D. Finally, the cumulative risk of the four SNPs was significantly associated with obesity (p: 1.95 × 10-4). CONCLUSION: Associations in FTO, ABCA, ADRB3, and PPARG SNPs presented in this study with obesity and metabolic syndrome could represent a risk for developing metabolic diseases in Northwest Mexican adult subjects.

Association of gene polymorphisms with women urinary incontinence.

Aim of study was set to investigate the association of women urinary incontinence (UI) with serotonin receptor HTR2A T102C and beta 3-adrenergic receptor ADRB3 Trp64Arg genes polymorphisms. The study included 110 women with Urge, Stress, and Mixed UI types and the control group - 105 continent women. Both groups have filled in the ICIQ-FLUTS questionnaire and their blood genotyping was performed. Urge UI subgroup was older and had higher body mass index (BMI) in comparison to other UI types and control group. More than half of all women had family history of UI in Stress UI and Mixed UI subgroups. The frequency of HTR2A T102C gene polymorphism's minor allele C and genotype CC was significantly more expressed in Urge UI subgroup, as compared with control group (C-77.3 vs 58.7%, p = 0.007 and CC-57.6 vs 31.1%, p = 0.015). The ADRB3 Trp64Arg gene polymorphism did not differ between groups. The regression analysis revealed CC genotype (OR = 3.06, 95% CI: 1.11-8.43; p = 0.030) and allele C (OR = 2.53, 95% CI: 1.16-5.53; p = 0.020) were risk factors for development of Urge UI. We conclude that HTR2A T102C gene polymorphism affected the development of Urge UI.

Proteomics analysis of adipose depots after intermittent fasting reveals visceral fat preservation mechanisms.

Intermittent fasting is a beneficial dietary treatment for obesity. But the response of each distinct adipose depot is currently poorly defined. Here we explore the response of key adipose depots to every-other-day fasting (EODF) in mice using proteomics. A key change in subcutaneous white adipose tissue (scWAT) and visceral WAT (vWAT) depots is an increase in mitochondrial protein content after EODF. This effect is correlated with increased fatty acid synthesis enzymes in both WAT depots but not in brown adipose tissue. Strikingly, EODF treatment downregulates lipolysis specifically in vWAT, mediated by a large decrease in the abundance of the catecholamine receptor (ADRB3). Together, these changes are important for preservation of the visceral lipid store during EODF. Enrichment analysis highlights downregulation of inflammatory collagen IV specifically in vWAT, allowing improved insulin sensitivity. This resource for adipose-depot-specific fasting adaptations in mice is available using a web-based interactive visualization.