Oxytocin and 'social hyperthermia': Interaction with ß3-adrenergic receptor-mediated thermogenesis and significance for the expression of social behavior in male and female mice.

Oxytocin (OT) is a critical regulator of multiple facets of energy homeostasis, including brown adipose tissue (BAT) thermogenesis. Nevertheless, it is unclear what, if any, consequence the thermoregulatory and metabolic effects of OT have for the display of social behavior in adult rodents. Here, we examine the contribution of the OT receptor (OTR) and ß3 adrenergic receptor (ß3AR) to the increase in body temperature that typically accompanies social interaction (i.e., social hyperthermia; SH) and whether SH relates to the expression of social behavior in adult mice. Specifically, we examined how OTR antagonism via peripheral injection of L-368,899 (10 mg/kg) affects the expression of social behavior in C57BL/6J mice, in the presence of active/agonized versus antagonized ß3AR, the receptor known to mediate stress-induced BAT thermogenesis. After drug treatment and a 30 min delay, mice were provided a 10 min social interaction test with an unfamiliar, same-sex conspecific. We hypothesized that OTR and ß3AR/BAT interact to influence behavior during social interaction, with at least some effects of OT on social behavior dependent upon OT's thermal effects via ß3AR/BAT. We found that OTR-mediated temperature elevation is largely responsible for SH during social interaction in mice-albeit not substantially via ß3AR-dependent BAT thermogenesis. Further, our results reveal a complex relationship between OTR, ß3AR, social hyperthermia and the display of specific social behaviors, with SH most closely associated with anxiety and/or vigilance-related behaviors-that is, behaviors that antagonize or interfere with the initiation of close, non-agonistic social behavior.

Functional Characterization of the Obesity-Linked Variant of the ß3-Adrenergic Receptor.

Adrenergic receptor ß3 (ADRß3) is a member of the rhodopsin-like G protein-coupled receptor family. The binding of the ligand to ADRß3 activates adenylate cyclase and increases cAMP in the cells. ADRß3 is highly expressed in white and brown adipocytes and controls key regulatory pathways of lipid metabolism. Trp64Arg (W64R) polymorphism in the ADRß3 is associated with the early development of type 2 diabetes mellitus, lower resting metabolic rate, abdominal obesity, and insulin resistance. It is unclear how the substitution of W64R affects the functioning of ADRß3. This study was initiated to functionally characterize this obesity-linked variant of ADRß3. We evaluated in detail the expression, subcellular distribution, and post-activation behavior of the WT and W64R ADRß3 using single cell quantitative fluorescence microscopy. When expressed in HEK 293 cells, ADRß3 shows a typical distribution displayed by other GPCRs with a predominant localization at the cell surface. Unlike adrenergic receptor ß2 (ADRß2), agonist-induced desensitization of ADRß3 does not involve loss of cell surface expression. WT and W64R variant of ADRß3 displayed comparable biochemical properties, and there was no significant impact of the substitution of tryptophan with arginine on the expression, cellular distribution, signaling, and post-activation behavior of ADRß3. The obesity-linked W64R variant of ADRß3 is indistinguishable from the WT ADRß3 in terms of expression, cellular distribution, signaling, and post-activation behavior.

Interaction between beta-3 adrenergic receptor genotype and environmental factors on periodontal progression.

OBJECTIVES: The purpose of this longitudinal study was to evaluate the relationship between beta-3 adrenergic receptor polymorphism and environmental factors such as smoking on periodontal disease by considering effect modification. MATERIALS AND METHODS: A total of 294 subjects who participated in all follow-up surveys over the 6-year study period were analysed. After dividing subjects into tertiles according to the number of years exposed to smoking, we conducted Poisson regression analysis to compare the incidence rate ratio (IRR) for periodontal disease events during the 6-year study period with beta-3 adrenergic receptor genotype (1: Arg allele carriers, 2: Arg allele non-carriers) for each tertile adjusted for other four variables. RESULTS: The number of years exposed to smoking (mean ± standard deviation) for the 1st, 2nd and 3rd tertiles was 0 ± 0, 20.1 ± 9.1 and 45.3 ± 7.7 years, respectively. The IRRs ± SE were 0.89 ± 0.08 (p = 0.218) for the 1st tertile, 1.93 ± 0.36 (p < 0.001) for the 2nd tertile and 2.56 ± 0.23 (p < 0.001) for the 3rd tertile. CONCLUSION: There was a clear dose-response relationship between beta-3 adrenergic receptor genotype and periodontal disease progression based on the number of years exposed to smoking.

Association between Beta3-Adrenergic Receptor Trp64Arg Polymorphism and Fat Preference in Healthy Young Japanese Women.

Beta3-adrenergic receptor (ADRB3) is a mediator of catecholamine-stimulated lipolysis in humans. The Trp64Arg polymorphism with T/C transition in the ADRB3 gene has been considered to reduce lipolysis and metabolic expenditure. Here, we investigated the hitherto unknown role of the Trp64Arg substitution on food preference among healthy young adults (mean age, 24.3; n = 53, including 25 men). Preference toward four food types (bitter, sour, salty, or sweet) and greasy (high-fat) foods was examined using a self-reported questionnaire. There was no noticeable sex-difference in food preference. Incidentally, only among female subjects, the genotype frequencies of the Trp64Arg polymorphism were in accordance with the Hardy-Weinberg equilibrium. Consequently, female subjects were divided into two groups for further analyses: 18 subjects with TT genotype (Trp64Trp) (wild-type group) and 10 subjects with TC genotype (Trp64Arg) (heterozygous group). No significant difference was observed in preference for four food types between the groups. However, when sweet foods were divided into high-fat and low-fat subgroups, food preference for high-fat sweet foods in heterozygous group was significantly higher than that in wild-type group. Moreover, when subjects were divided into two classes based on preference for greasy foods (like, n = 16 or dislike, n = 12), the preference degree in heterozygous group who liked high-fat foods (n = 5) was significantly higher than that in wild-type group (n = 11), suggesting that the Trp64Arg substitution might genetically enhance high-fat food preference. Thus, understanding the relationship between ADRB3 Trp64Arg substitution and fat preference will be valuable for obesity prevention.

Beta3 adrenergic receptor stimulation in human macrophages inhibits NADPHoxidase activity and induces catalase expression via PPARγ activation.

The beta3 adrenergic receptor (ß3-AR) stimulation plays a protective role against preterm labor by blocking myometrial contraction, cytokine production, remodeling and apoptosis. We previously demonstrated that macrophage-induced ROS production in the myometrium was a key element leading to the induction of all these labor-associated features. We thus aimed to investigate if the ß3-AR could be expressed in human macrophages and could trigger its protective role in the myometrium by directly inhibiting ROS production. Using lipopolysaccharide (LPS)-stimulated myometrial samples and cell co-culture experiments, we demonstrated that ß3-AR stimulation inhibits the activation of the NADPH oxidase, leading to the subsequent inhibition of ROS production by macrophages. This antioxidant effect was associated with a potent anti-inflammatory response in macrophages. Furthermore, we observed that ß3-AR leads to the expression of catalase not only in macrophages but also in myometrial cells, thereby preventing the transactivation of myometrial cells by hydrogen peroxide. Pharmacological experiments allowed us to demonstrate that these effects were driven by an Erk1/2-mediated activation of the antioxidant transcription factor PPARγ. These results suggest that ß3-AR protective effects in the myometrium could be due to its dual antioxidant properties. Further, the effects observed in a macrophage could highlight new applications in chronic inflammatory diseases.

[Rationale of efficiency and safety of using beta3-adrenergic receptor agonist for treatment of overactive bladder].

Currently, antimuscarinics are the most commonly used drugs for the treatment of overactive bladder (OAB). Improving quality of life and treatment satisfaction are key factors for adherence to therapy. Mirabegron, the first drug in the class of b3-adrenergic receptor agonists, is used as an alternative to antimuscarinic drugs in the treatment of OAB and it has proved efficacy and excellent safety profile. Observational studies can provide data on the efficiency of therapy in routine clinical practice, and real-life data indicate that the duration of treatment with mirabegron may be longer compared with that of antimuscarinic drugs. A prospective study (BELIEVE) has been the largest European study which evaluated quality of life, treatment satisfaction and adherence to therapy in patients with OAB who were prescribed mirabegron in routine clinical practice. The BELIEVE study has been approved by regulatory authorities in all participating countries based on local requirements. The primary end point was to evaluate the change in quality of life compared to baseline based on the OAB questionnaire. Secondary end points included evaluating treatment duration, patient satisfaction, use of health resources, and side effects. Subsequent observation was provided for 12 months with follow-up visits after 2-4 and 10-12 months of therapy. A total of 862 862 patients from 8 European countries were included in the study. 73.7% of patients were women, and the average age was 61.2 years; 47.7% of patients were older than 65 years. At the beginning of the study, 41.3% of patients preferred other types of treatment, 42.2% were treatment-nave, 10.1% dropped out of the study, 6.4% received combination therapy. Storage symptoms and general quality of life improved from baseline to 2-4 and 10-12 months. There was a marked improvement in continence rate, increasing from 34.9% at the beginning to 43.7% after 10-12 months, and the use of pads decreased. Adherence to therapy was at a high level: 53.8% of patients continued taking mirabegron after 10-12 months. In general, no unexpected adverse events were observed, and they were consistent with the described safety profile of mirabegron. Patients receiving mirabegron reported a significant improvement in their quality of life and health status, while the level of adherence for the drug was 53.8% for 12 months. No unexpected safety problems were found, and side effects were consistent with previously described safety profile.

NT-PGC-1α deficiency decreases mitochondrial FA oxidation in brown adipose tissue and alters substrate utilization in vivo.

Transcriptional coactivator PPAR γ coactivator (PGC)-1α and its splice variant N-terminal (NT)-PGC-1α mediate transcriptional regulation of brown adipose tissue (BAT) thermogenesis in response to changes in ambient temperature. PGC-1α is dispensable for cold-induced BAT thermogenesis as long as NT-PGC-1α is present. However, the functional significance of NT-PGC-1α in BAT has not been determined. In the present study, we generated NT-PGC-1α-/- mice to investigate the effect of NT-PGC-1α deficiency on adaptive BAT thermogenesis. At thermoneutrality, NT-PGC-1α-/- mice exhibited abnormal BAT phenotype with increased accumulation of large lipid droplets concomitant with marked downregulation of FA oxidation (FAO)-related genes. Consistent with transcriptional changes, mitochondrial FAO was significantly diminished in NT-PGC-1α-/- BAT. This alteration, in turn, enhanced glucose utilization within the NT-PGC-1α-/- BAT mitochondria. In line with this, NT-PGC-1α-/- mice had higher reliance on carbohydrates. In response to cold or ß3-adrenergic receptor agonist, NT-PGC-1α-/- mice transiently exhibited lower thermogenesis but reached similar thermogenic capacities as their WT littermates. Collectively, these findings demonstrate that NT-PGC-1α is an important contributor to the maintenance of FAO capacity in BAT at thermoneutrality and provide deeper insights into the relative contributions of PGC-1α and NT-PGC-1α to temperature-regulated BAT remodeling.

Sustained stimulation of ß2- and ß3-adrenergic receptors leads to persistent functional pain and neuroinflammation.

Functional pain syndromes, such as fibromyalgia and temporomandibular disorder, are associated with enhanced catecholamine tone and decreased levels of catechol-O-methyltransferase (COMT; an enzyme that metabolizes catecholamines). Consistent with clinical syndromes, our lab has shown that sustained 14-day delivery of the COMT inhibitor OR486 in rodents results in pain at multiple body sites and pain-related volitional behaviors. The onset of COMT-dependent functional pain is mediated by peripheral ß2- and ß3-adrenergic receptors (ß2- and ß3ARs) through the release of the pro-inflammatory cytokines tumor necrosis factor α (TNFα), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6). Here, we first sought to investigate the role of ß2- and ß3ARs and downstream mediators in the maintenance of persistent functional pain. We then aimed to characterize the resulting persistent inflammation in neural tissues (neuroinflammation), characterized by activated glial cells and phosphorylation of the mitogen-activated protein kinases (MAPKs) p38 and extracellular signal-regulated kinase (ERK). Separate groups of rats were implanted with subcutaneous osmotic mini-pumps to deliver OR486 (15 mg/kg/day) or vehicle for 14 days. The ß2AR antagonist ICI118551 and ß3AR antagonist SR59230A were co-administrated subcutaneously with OR486 or vehicle either on day 0 or day 7. The TNFα inhibitor Etanercept, the p38 inhibitor SB203580, or the ERK inhibitor U0126 were delivered intrathecally following OR486 cessation on day 14. Behavioral responses, pro-inflammatory cytokine levels, glial cell activation, and MAPK phosphorylation were measured over the course of 35 days. Our results demonstrate that systemic delivery of OR486 leads to mechanical hypersensitivity that persists for at least 3 weeks after OR486 cessation. Corresponding increases in spinal TNFα, IL-1ß, and IL-6 levels, microglia and astrocyte activation, and neuronal p38 and ERK phosphorylation were observed on days 14-35. Persistent functional pain was alleviated by systemic delivery of ICI118551 and SR59230A beginning on day 0, but not day 7, and by spinal delivery of Etanercept or SB203580 beginning on day 14. These results suggest that peripheral ß2- and ß3ARs drive persistent COMT-dependent functional pain via increased activation of immune cells and production of pro-inflammatory cytokines, which promote neuroinflammation and nociceptor activation. Thus, therapies that resolve neuroinflammation may prove useful in the management of functional pain syndromes.

Meta-analysis of the association between the Trp64Arg polymorphism of the beta-3 adrenergic receptor and susceptibility to gestational diabetes mellitus.

The study aimed to explore the associations between Trp64Arg polymorphism of Beta-3 Adrenergic receptor (ADRB3) and susceptibility to gestational diabetes mellitus (GDM). Relevant studies till December 2013 were identified through searching electronic databases. A meta-analysis was conducted on associations between Trp64Arg polymorphism in ADRB3 and susceptibility to GDM. We found no association between Trp64Arg polymorphism in ADRB3 and susceptibility to GDM in overall population (Arg vs. Trp: OR = 1.20, 95%CI = 0.99-1.47, p = .16; Trp/Arg + Arg/Arg vs. Trp/Trp: OR = 1.22, 95%CI = 0.99-1.50, p = .11). In subgroup analysis on European Caucasian population, Trp64Arg in ADRB3 was associated with susceptibility to GDM. Trp64Arg polymorphism in ADRB3 had certain association with susceptibility to GDM in the European Caucasian population. Impact statement What is already known on this subject: Gestational diabetes mellitus (GDM) is recognised as carbohydrate intolerance of varied severity that begins or is first recognised during pregnancy. A missense mutation in the codon 64 of the Beta-3 adrenergic receptor (ADRB3), Trp64Arg, leads to the substitution of tryptophan by arginine in the first intracellular loop of the ADRB3 receptor. Trp64Arg Polymorphism has also been reportedly associated with increased body weight, type 2 diabetes mellitus, insulin resistance and obesity. However, other investigators have found that the Trp64Arg polymorphism of ADRB3 has no effect on insulin resistance, obesity or type 2 diabetes mellitus. What the results of the study add: Our present meta-analysis demonstrated that Trp64Arg polymorphism in ADRB3 was associated with susceptibility to GDM in the European Caucasian population. Trp64Arg polymorphism in ADRB3 may be able to predict the occurrence of GDM and used for the diagnosis of it in clinic. What the implications are of these findings for clinical practice and future research: The findings in this study may provide a basis for the further study on Trp64Arg polymorphism in future research.

Relationship between renal function and periodontal disease in community-dwelling elderly women with different genotypes.

OBJECTIVES: The aim of this study was to examine the association between periodontal disease and renal function in elderly women with different genotypes. MATERIAL AND METHODS: A total of 332 postmenopausal never-smoking women were analysed. Poor renal function was defined as serum cystatin C > 0.91 mg/l. Periodontal disease markers such as periodontal inflamed surface area (PISA) were evaluated. Selected variables, including PISA quartile, body mass index (BMI), HbA1C and age in Arg allele carriers and non-carriers based on the beta-3 adrenergic receptor, or between Ala allele carriers and non-carriers based on peroxisome proliferator-activated receptor gamma, were analysed using multiple logistic regression analysis. RESULTS: The odds ratios of serum cystatin C level and PISA (fourth quartile) were significantly positive for both Arg (2.52; p = 0.035) and Ala allele non-carriers (2.36; p = 0.021). A significant association was also found between serum cystatin C level and BMI for both Arg (1.18; p = 0.001) and Ala allele non-carriers (1.12; p = 0.003). CONCLUSION: The results of this study suggest that periodontal inflammation might be associated with renal function. Furthermore, in both the Arg and Ala allele non-carriers, the associations between BMI and PISA for renal function became stronger.

2D-QSAR and 3D-QSAR/CoMSIA Studies on a Series of (R)-2-((2-(1H-Indol-2-yl)ethyl)amino)-1-Phenylethan-1-ol with Human ß3-Adrenergic Activity.

The ß3 adrenergic receptor is raising as an important drug target for the treatment of pathologies such as diabetes, obesity, depression, and cardiac diseases among others. Several attempts to obtain selective and high affinity ligands have been made. Currently, Mirabegron is the only available drug on the market that targets this receptor approved for the treatment of overactive bladder. However, the FDA (Food and Drug Administration) in USA and the MHRA (Medicines and Healthcare products Regulatory Agency) in UK have made reports of potentially life-threatening side effects associated with the administration of Mirabegron, casting doubts on the continuity of this compound. Therefore, it is of utmost importance to gather information for the rational design and synthesis of new ß3 adrenergic ligands. Herein, we present the first combined 2D-QSAR (two-dimensional Quantitative Structure-Activity Relationship) and 3D-QSAR/CoMSIA (three-dimensional Quantitative Structure-Activity Relationship/Comparative Molecular Similarity Index Analysis) study on a series of potent ß3 adrenergic agonists of indole-alkylamine structure. We found a series of changes that can be made in the steric, hydrogen-bond donor and acceptor, lipophilicity and molar refractivity properties of the compounds to generate new promising molecules. Finally, based on our analysis, a summary and a regiospecific description of the requirements for improving ß3 adrenergic activity is given.

Beta-3 adrenergic agonists reduce pulmonary vascular resistance and improve right ventricular performance in a porcine model of chronic pulmonary hypertension.

Beta-3 adrenergic receptor (ß3AR) agonists have been shown to produce vasodilation and prevention of ventricular remodeling in different conditions. Given that these biological functions are critical in pulmonary hypertension (PH), we aimed to demonstrate a beneficial effect of ß3AR agonists in PH. An experimental study in pigs (n = 34) with chronic PH created by pulmonary vein banding was designed to evaluate the acute hemodynamic effect and the long-term effect of ß3AR agonists on hemodynamics, vascular remodeling and RV performance in chronic PH. Ex vivo human experiments were performed to explore the expression of ß3AR mRNA and the vasodilator response of ß3AR agonists in pulmonary arteries. Single intravenous administration of the ß3AR agonist BRL37344 produced a significant acute reduction in PVR, and two-weeks treatment with two different ß3AR selective agonists, intravenous BRL37344 or oral mirabegron, resulted in a significant reduction in PVR (median of -2.0 Wood units/m(2) for BRL37344 vs. +1.5 for vehicle, p = 0.04; and -1.8 Wood units/m(2) for mirabegron vs. +1.6 for vehicle, p = 0.002) associated with a significant improvement in magnetic resonance-measured RV performance. Histological markers of pulmonary vascular proliferation (p27 and Ki67) were significantly attenuated in ß3AR agonists-treated pigs. ß3AR was expressed in human pulmonary arteries and ß3AR agonists produced vasodilatation. ß3AR agonists produced a significant reduction in PVR and improved RV performance in experimental PH, emerging as a potential novel approach for treating patients with chronic PH.

Adipocyte lipolysis-stimulated interleukin-6 production requires sphingosine kinase 1 activity.

Adipocyte lipolysis can increase the production of inflammatory cytokines such as interleukin-6 (IL-6) that promote insulin resistance. However, the mechanisms that link lipolysis with inflammation remain elusive. Acute activation of ß3-adrenergic receptors (ADRB3) triggers lipolysis and up-regulates production of IL-6 in adipocytes, and both of these effects are blocked by pharmacological inhibition of hormone-sensitive lipase. We report that stimulation of ADRB3 induces expression of sphingosine kinase 1 (SphK1) and increases sphingosine 1-phosphate production in adipocytes in a manner that also depends on hormone-sensitive lipase activity. Mechanistically, we found that adipose lipolysis-induced SphK1 up-regulation is mediated by the c-Jun N-terminal kinase (JNK)/activating protein-1 signaling pathway. Inhibition of SphK1 by sphingosine kinase inhibitor 2 diminished the ADRB3-induced IL-6 production both in vitro and in vivo. Induction of IL-6 by ADRB3 activation was suppressed by siRNA knockdown of Sphk1 in cultured adipocytes and was severely attenuated in Sphk1 null mice. Conversely, ectopic expression of SphK1 increased IL-6 expression in adipocytes. Collectively, these data demonstrate that SphK1 is a critical mediator in lipolysis-triggered inflammation in adipocytes.

Adipose tissue plasticity from WAT to BAT and in between.

Adipose tissue plays an essential role in regulating energy balance through its metabolic, cellular and endocrine functions. Adipose tissue has been historically classified into anabolic white adipose tissue and catabolic brown adipose tissue. An explosion of new data, however, points to the remarkable heterogeneity among the cells types that can become adipocytes, as well as the inherent metabolic plasticity of mature cells. These data indicate that targeting cellular and metabolic plasticity of adipose tissue might provide new avenues for treatment of obesity-related diseases. This review will discuss the developmental origins of adipose tissue, the cellular complexity of adipose tissues, and the identification of progenitors that contribute to adipogenesis throughout development. We will touch upon the pathological remodeling of adipose tissue and discuss how our understanding of adipose tissue remodeling can uncover new therapeutic targets. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.

Medium-Chain Triglyceride Activated Brown Adipose Tissue and Induced Reduction of Fat Mass in C57BL/6J Mice Fed High-fat Diet.

OBJECTIVE: To investigate activation of brown adipose tissue (BAT) stimulated by medium-chain triglyceride (MCT). METHODS: 30 Male C57BL/6J obese mice induced by fed high fat diet (HFD) were divided into 2 groups, and fed another HFD with 2% MCT or long-chain triglyceride (LCT) respectively for 12 weeks. Body weight, blood biochemical variables, interscapular brown fat tissue (IBAT) mass, expressions of mRNA and protein of beta 3-adrenergic receptors (ß3-AR), uncoupling protein-1 (UCP1), hormone sensitive lipase (HSL), protein kinase A (PKA), and adipose triglyceride lipase (ATGL) in IBAT were measured. RESULTS: Significant decrease in body weight and body fat mass was observed in MCT group as compared with LCT group (P<0.05) after 12 weeks. Greater increases in IBAT mass was observed in MCT group than in LCT group (P<0.05). Blood TG, TC, LDL-C in MCT group were decreased significantly, meanwhile blood HDL-C, ratio of HDL-C/LDL-C and norepinephrine were increased markedly. Expressions of mRNA and protein of ß3-AR, UCP1, PKA, HSL, ATGL in BAT were greater in MCT group than in LCT group (P<0.05). CONCLUSION: Our results suggest that MCT stimulated the activation of BAT, possible via norepinephrine pathway, which might partially contribute to reduction of the body fat mass in obese mice fed high fat diet.

The interaction between beta-3 adrenergic receptor polymorphism and obesity to periodontal disease in community-dwelling elderly Japanese.

OBJECTIVES: The purpose of this study was to elucidate whether the association between beta-3 adrenergic receptor polymorphism and periodontal disease is modified by body weight. MATERIAL AND METHODS: We enrolled 332 postmenopausal women and determined their HbA1C levels (%) and beta-3 adrenergic receptor (rs4994) genotypes. Periodontal parameters including clinical attachment level (CAL) were measured. After selecting subjects for each body mass index (BMI) level, the prevalence rate ratio (PRR) by multiple Poisson regression analysis was calculated to evaluate the relationship between periodontal disease and beta-3 adrenergic receptor polymorphism. The number of sites with CAL≥6 mm was used as a dependent variable, and beta-3 adrenergic receptor genotype [categorized as Arg non-carriers (reference) or Arg carriers], age (y) and HbA1C (%) were adopted as independent variables. We converted the number of probing sites (n) to an offset variable. RESULTS: The PRR of the beta-3 adrenergic receptor genotype for the number of sites of CAL≥6 mm showed a positive association in subjects with BMI≥25.0 and increased markedly with BMI. The PRR in subjects with BMI≥30 was 3.10 (p < 0.0001). CONCLUSION: This study indicates a positive association between periodontal disease and the beta-3 adrenergic receptor genotype in obese individuals.

A Plain Language Summary on the Effect of the Medication Vibegron on Blood Pressure and Heart Rate in People With Overactive Bladder.

WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of an article originally published in the journal Blood Pressure Monitoring. Vibegron is a medicine that was approved by the US Food and Drug Administration (also called FDA) in 2020 for treatment of overactive bladder, a condition that causes a frequent and urgent need to urinate. This study took place before the medicine was approved to look at whether vibegron affects blood pressure or heart rate. WHAT WERE THE RESULTS?: A total of 214 patients with overactive bladder took part in the study. 108 patients took vibegron for 28 days, and 106 took placebo for 28 days. A placebo is a pill with no medicine in it. Their blood pressure was measured on the first day and the last day. A meaningful increase in blood pressure is when a patient's average blood pressure measurements changed by 3.5 mmHg or more. Patients with overactive bladder who took a 75 mg dose of vibegron once daily had no meaningful increase in blood pressure or heart rate. This included people who were already taking medication for their high blood pressure. WHAT DO THE RESULTS MEAN?: This study suggests that patients can use vibegron without concern that it may meaningfully raise blood pressure or heart rate.

Plain language summary: does treatment with vibegron result in improvements in overactive bladder (OAB) symptoms that are meaningful to people with OAB?

What is this summary about? This is a plain language summary of an article published in the journal Advances in Therapy. In 2020, the US Food and Drug Administration (also called the FDA) approved a medicine called vibegron to treat overactive bladder, also called OAB. The key results used to approve vibegron were from the EMPOWUR study. In the EMPOWUR study, participants who took vibegron had fewer urination episodes, urgency episodes, and bladder leaks each day than those who took a pill containing no medicine, called a placebo. At the end of the study, participants also rated how much their overactive bladder symptoms changed overall during EMPOWUR by responding to a survey. Many participants rated their overactive bladder symptoms as improved overall. This study asked if improvements in the number of urination episodes, urgency episodes, and bladder leaks caused by urgency were associated with feeling better overall. This study also looked at how many participants in the EMPOWUR study had improvements in the number of urination episodes, urgency episodes, and bladder leaks that were big enough to matter. A separate group of people with overactive bladder were asked about the magnitude of improvements that would be important to them. This group had not participated in the EMPOWUR study. What were the results? EMPOWUR participants who reported that taking medicine resulted in their overactive bladder symptoms getting better overall also generally reported fewer daily urinations, urgency episodes, and bladder leaks after treatment. Many had changes in their symptoms that were meaningful. Meaningful was defined for each symptom as: at least 15% fewer urinations, 50% fewer urgency episodes, and 75% fewer bladder leaks. Participants who received vibegron had meaningful reductions in the daily number of episodes of urination, urgency, and bladder leaks more often than those who received the placebo (pill with no active medicine). People with overactive bladder who did not participate in the study were interviewed and said that improvements to those symptoms, similar to those seen in the EMPOWUR study, would be important to them. What do the results mean? This study suggests that the results we measured in the EMPOWUR study may also reflect changes in overactive bladder symptoms that are big enough to be important to people with overactive bladder. Many participants who took vibegron in the EMPOWUR study felt that it helped to improve their individual overactive bladder symptoms. This may also help improve quality of life of participants. Clinical Trial Registration: NCT03492281 (ClinicalTrials.gov).

Plain language summary of safety and symptom improvement with vibegron in people with overactive bladder: results from the EMPOWUR study.

What is this summary about? This is a plain language summary of an article originally published in the Journal of Urology. Overactive bladder (also called OAB) has been treated with the same type of medicine for more than 40 years. Vibegron is in a newer class of medicine for treating overactive bladder called beta-3 adrenergic receptor agonists. The EMPOWUR study was a phase 3 clinical trial that looked at whether vibegron was safe and improved symptoms in people with overactive bladder. Vibegron was approved by the US Food and Drug Administration (also called the FDA) based in part on the results of this study. What were the results? Participants of the EMPOWUR study who took vibegron showed an improvement in their overactive bladder symptoms. These symptoms include the number of urinations (peeing), the urgent need to urinate, and accidental urination (bladder leaks). After 12 weeks, participants who took vibegron had significantly greater improvements than participants who took placebo. What do the results mean? This study suggests that vibegron could safely improve symptoms in people with overactive bladder. Clinical Trial Registration: NCT03492281 (ClinicalTrials.gov).

Association Between Trp64Arg Polymorphism of Beta-3 Adrenergic Receptor Gene and Susceptibility to Overactive Bladder: A Meta-Analysis.

Objective: Some studies have been carried out to investigate the association between Trp64Arg polymorphism in beta-3 adrenergic receptor gene (ADRB3) and susceptibility to overactive bladder (OAB), but the results remain inconsistent. We carried out a meta-analysis to acquire a more accurate estimation. Methods: All eligible studies were searched in PubMed, Web of Science, Embase, and Cochrane Library. Pooled odds ratios, with 95% confidence intervals, were assessed for the association using fixed and random effects models. Results: The overall results of this meta-analysis demonstrated that there might be an association between Trp64Arg polymorphism and susceptibility to OAB in allele model, dominant model, and heterozygote comparison with a relative risk of 2.00 (95% CI 1.36-2.93), 2.13 (95% CI 1.20-3.76), and 2.07 (95% CI: 1.13-3.79), respectively. However, in the recessive model and homozygote comparison, no significant association between ESR1 Trp64Arg polymorphism and susceptibility to OAB was observed, with a relative risk of 2.47 (95% CI 0.63-9.73) and 3.12 (95% CI: 0.79-12.35), respectively. Based on trail sequential analysis, the results turned out to be true positive in the allele model, false positive in the dominant model and heterozygote comparison, and negative in the recessive model and homozygote comparison, respectively. Conclusion: Our analysis indicated that Trp64Arg polymorphisms in ADRB3 might increase the risk of OAB twice in the allele model, but further well-designed studies with large sample sizes are required to confirm the present findings in other modes and comparisons.