RESUMEN
Adipose tissue beiging refers to the process by which beige adipocytes emerge in classical white adipose tissue depots. Beige adipocytes dissipate chemical energy and secrete adipokines, such as classical brown adipocytes, to improve systemic metabolism, which is beneficial for people with obesity and metabolic diseases. Cold exposure and ß3-adrenergic receptor (AR) agonist treatment are two commonly used stimuli for increasing beige adipocytes in mice; however, their underlying biological processes are different. Transcriptional analysis of inguinal white adipose tissue (iWAT) has revealed that changes in extracellular matrix (ECM) pathway genes are specific to cold exposure. Hyaluronic acid (HA), a non-sulfated linear polysaccharide produced by nearly all cells, is one of the most common components of ECM. We found that cold exposure significantly increased iWAT HA levels, whereas the ß3-AR agonist CL316,243 did not. Increasing HA levels in iWAT by Has2 overexpression significantly increases cold-induced adipose tissue beiging; in contrast, decreasing HA by Spam1 overexpression, which encodes a hyaluronidase that digests HA, significantly decreases cold-induced iWAT beiging. All these data implicate a role of HA in promoting adipose tissue beiging, which is unique to cold exposure. Given the failure of ß3-AR agonists in clinical trials for obesity and metabolic diseases, increasing HA could serve as a new approach for recruiting more beige adipocytes to combat metabolic diseases.
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Tejido Adiposo Blanco , Frío , Ácido Hialurónico , Ácido Hialurónico/metabolismo , Animales , Ratones , Tejido Adiposo Blanco/metabolismo , Tejido Adiposo Blanco/efectos de los fármacos , Ratones Endogámicos C57BL , Masculino , Tejido Adiposo Beige/metabolismo , Adipocitos Beige/metabolismo , Adipocitos Beige/efectos de los fármacos , Matriz Extracelular/metabolismo , Dioxoles/farmacología , Receptores Adrenérgicos beta 3/metabolismo , Agonistas de Receptores Adrenérgicos beta 3/farmacologíaRESUMEN
Purpose: In response to hypoxia, sympathetic fibers to the retina activate ß-adrenoceptors (ß-ARs) that play an important role in the regulation of vascular and neuronal functions. We investigated the role of ß3-AR using the mouse model of oxygen-induced retinopathy (OIR). Methods: Mouse pups were exposed to 75% oxygen at postnatal day 7 (PD7) followed by a return to room air at PD12. The ß3-AR preferential agonist BRL37344 was subcutaneously administered once daily at different times after the return to room air. At PD17, the OIR mice underwent flash and pattern electroretinogram. After sacrifice, retinal wholemounts were used for vessel staining or immunohistochemistry for astrocytes, Müller cells, or retinal ganglion cells (RGCs). In retinal homogenates, the levels of markers associated with neovascularization (NV), the blood-retinal barrier (BRB), or astrocytes were determined by western blot, and quantitative reverse-transcription polymerase chain reaction was used to assess ß3-AR messenger. Administration of the ß3-AR antagonist SR59230A was performed to verify BRL37344 selectivity. Results: ß3-AR expression is upregulated in response to hypoxia, but its increase is prevented by BRL37344, which counteracts NV by inhibiting the pro-angiogenic pathway, activating the anti-angiogenic pathway, recovering BRB-associated markers, triggering nitric oxide production, and favoring revascularization of the central retina through recovered density of astrocytes that ultimately counteracts NV in the midperiphery. Vasculature rescue prevents dysfunctional retinal activity and counteracts OIR-associated retinal ganglion cell loss. Conclusions: ß3-AR has emerged as a crucial intermediary in hypoxia-dependent NV, suggesting a role of ß3-AR agonists in the treatment of proliferative retinopathies.
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Agonistas de Receptores Adrenérgicos beta 3 , Modelos Animales de Enfermedad , Electrorretinografía , Ratones Endogámicos C57BL , Oxígeno , Receptores Adrenérgicos beta 3 , Neovascularización Retiniana , Animales , Ratones , Neovascularización Retiniana/metabolismo , Neovascularización Retiniana/prevención & control , Neovascularización Retiniana/patología , Oxígeno/toxicidad , Agonistas de Receptores Adrenérgicos beta 3/farmacología , Receptores Adrenérgicos beta 3/metabolismo , Animales Recién Nacidos , Células Ganglionares de la Retina/patología , Células Ganglionares de la Retina/efectos de los fármacos , Células Ganglionares de la Retina/metabolismo , Etanolaminas/farmacología , Vasos Retinianos/efectos de los fármacos , Retinopatía de la Prematuridad/metabolismo , Retinopatía de la Prematuridad/tratamiento farmacológico , Astrocitos/metabolismo , Astrocitos/efectos de los fármacos , Inmunohistoquímica , AngiogénesisRESUMEN
OBJECTIVE AND DESIGN: Kinin B1 receptor (B1R) has a key role in adipocytes to protect against obesity and glycemic metabolism, thus becoming a potential target for regulation of energy metabolism and adipose tissue thermogenesis. MATERIAL OR SUBJECTS: Kinin B1 knockout mice (B1KO) were subjected to acute induction with CL 316,243 and chronic cold exposure. METHODS: Metabolic and histological analyses, gene and protein expression and RNA-seq were performed on interscapular brown adipose tissue (iBAT) and inguinal white adipose tissue (iWAT) of mice. RESULTS: B1KO mice, under acute effect of CL 316,243, exhibited increased energy expenditure and upregulated thermogenic genes in iWAT. They were also protected from chronic cold, showing enhanced non-shivering thermogenesis with increased iBAT mass (~ 90%) and recruitment of beige adipocytes in iWAT (~ 50%). Positive modulation of thermogenic and electron transport chain genes, reaching a 14.5-fold increase for Ucp1 in iWAT. RNA-seq revealed activation of the insulin signaling pathways for iBAT and oxidative phosphorylation, tricarboxylic acid cycle, and browning pathways for iWAT. CONCLUSION: B1R deficiency induced metabolic and gene expression alterations in adipose tissue, activating thermogenic pathways and increasing energy metabolism. B1R antagonists emerge as promising therapeutic targets for regulating obesity and associated metabolic disorders, such as inflammation and diabetes.
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Tejido Adiposo Pardo , Tejido Adiposo Blanco , Dioxoles , Ratones Noqueados , Receptor de Bradiquinina B1 , Termogénesis , Animales , Termogénesis/efectos de los fármacos , Receptor de Bradiquinina B1/genética , Receptor de Bradiquinina B1/metabolismo , Dioxoles/farmacología , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Pardo/efectos de los fármacos , Masculino , Tejido Adiposo Blanco/metabolismo , Tejido Adiposo Blanco/efectos de los fármacos , Ratones , Metabolismo Energético/efectos de los fármacos , Ratones Endogámicos C57BL , Tiazoles/farmacología , Agonistas de Receptores Adrenérgicos beta 3/farmacología , Frío , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo , Receptores Adrenérgicos beta 3/genética , Receptores Adrenérgicos beta 3/metabolismoRESUMEN
BACKGROUND: Sympathetic activation of brown adipose tissue (BAT) thermogenesis can ameliorate obesity and related metabolic abnormalities. However, crucial subtypes of the ß-adrenergic receptor (AR), as well as effects of its genetic variants on functions of BAT, remains unclear in humans. We conducted association analyses of genes encoding ß-ARs and BAT activity in human adults. METHODS: Single nucleotide polymorphisms (SNPs) in ß1-, ß2-, and ß3-AR genes (ADRB1, ADRB2, and ADRB3) were tested for the association with BAT activity under mild cold exposure (19 °C, 2 h) in 399 healthy Japanese adults. BAT activity was measured using fluorodeoxyglucose-positron emission tomography and computed tomography (FDG-PET/CT). To validate the results, we assessed the effects of SNPs in the two independent populations comprising 277 healthy East Asian adults using near-infrared time-resolved spectroscopy (NIRTRS) or infrared thermography (IRT). Effects of SNPs on physiological responses to intensive cold exposure were tested in 42 healthy Japanese adult males using an artificial climate chamber. RESULTS: We found a significant association between a functional SNP (rs1042718) in ADRB2 and BAT activity assessed with FDG-PET/CT (p < 0.001). This SNP also showed an association with cold-induced thermogenesis in the population subset. Furthermore, the association was replicated in the two other independent populations; BAT activity was evaluated by NIRTRS or IRT (p < 0.05). This SNP did not show associations with oxygen consumption and cold-induced thermogenesis under intensive cold exposure, suggesting the irrelevance of shivering thermogenesis. The SNPs of ADRB1 and ADRB3 were not associated with these BAT-related traits. CONCLUSIONS: The present study supports the importance of ß2-AR in the sympathetic regulation of BAT thermogenesis in humans. The present collection of DNA samples is the largest to which information on the donor's BAT activity has been assigned and can serve as a reference for further in-depth understanding of human BAT function.
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Tejido Adiposo Pardo , Polimorfismo de Nucleótido Simple , Receptores Adrenérgicos beta 2 , Termogénesis , Humanos , Termogénesis/fisiología , Termogénesis/genética , Tejido Adiposo Pardo/metabolismo , Masculino , Adulto , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 2/metabolismo , Femenino , Persona de Mediana Edad , Japón , Tomografía Computarizada por Tomografía de Emisión de Positrones , Receptores Adrenérgicos beta 3/genética , Receptores Adrenérgicos beta 3/metabolismo , Pueblo Asiatico/genéticaRESUMEN
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.
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Adipocitos Beige , Frío , Receptores Adrenérgicos beta 3 , Animales , Receptores Adrenérgicos beta 3/metabolismo , Receptores Adrenérgicos beta 3/genética , Adipocitos Beige/metabolismo , Porcinos , Adipogénesis/genética , Lipólisis , Termogénesis/genética , Diferenciación Celular , Mitocondrias/metabolismoRESUMEN
ABSTRACT: ß 3 -adrenergic receptor (ß 3 -AR) has been proposed as a new therapy for several myocardial diseases. However, the effect of ß 3 -AR activation on sepsis-induced myocardial apoptosis is unclear. Here, we investigated the effect of ß 3 -AR activation on the cardiomyocyte apoptosis and cardiac dysfunction in cecal ligation and puncture (CLP)-operated rats and lipopolysaccharide (LPS)-treated cardiomyocytes. We found that ß 3 -AR existed both in adult rat ventricular myocytes (ARVMs) and H9c2 cells. The expression of ß 3 -AR was upregulated in LPS-treated ARVMs and the heart of CLP rats. Pretreatment with ß 3 -AR agonist, BRL37344, inhibited LPS-induced cardiomyocyte apoptosis and caspase-3, -8, and -9 activation in ARVMs. BRL37344 also reduced apoptosis and increased the protein levels of PI3K, p-Akt Ser473 and p-eNOS Ser1177 in LPS-treated H9c2 cells. Inhibition of PI3K using LY294002 abolished the inhibitory effect of BRL37344 on LPS-induced caspase-3, -8, and -9 activation in H9c2 cells. Furthermore, administration of ß 3 -AR antagonist, SR59230A (5 mg/kg), significantly decreased the maximum rate of left ventricular pressure rise (+dP/dt) in CLP-induced septic rats. SR59230A not only increased myocardial apoptosis, reduced p-Akt Ser473 and Bcl-2 contents, but also increased mitochondrial Bax, cytoplasm cytochrome c, cleaved caspase-9, and cleaved caspase-3 levels of the myocardium in septic rats. These results suggest that endogenous ß 3 -AR activation alleviates sepsis-induced cardiomyocyte apoptosis via PI3K/Akt signaling pathway and maintains intrinsic myocardial systolic function in sepsis.
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Apoptosis , Miocitos Cardíacos , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Ratas Sprague-Dawley , Receptores Adrenérgicos beta 3 , Sepsis , Transducción de Señal , Animales , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/patología , Apoptosis/efectos de los fármacos , Sepsis/metabolismo , Ratas , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos , Masculino , Receptores Adrenérgicos beta 3/metabolismo , Lipopolisacáridos/toxicidad , Agonistas de Receptores Adrenérgicos beta 3/farmacología , Línea Celular , EtanolaminasRESUMEN
Sex differences are consistently identified in determining the prevalence, manifestation, and response to therapies in several systemic disorders, including those affecting the cardiovascular (CV), skeletal muscle, and nervous system. Interestingly, such differences are often more noticeable as we age. For example, premenopausal women experience a lower risk of CV disease than men of the same age. While at an advanced age, with menopause, the risk of cardiovascular diseases and adverse outcomes increases exponentially in women, exceeding that of men. However, this effect appears to be reversed in diseases such as pulmonary hypertension, where women are up to seven times more likely than men to develop an idiopathic form of the disease with symptoms developing ten years earlier than their male counterparts. Explaining this is a complex question. However, several factors and mechanisms have been identified in recent decades, including a role for sex hormones, particularly estrogens and their related receptors. Furthermore, an emerging role in these sex differences has also been suggested for ß-adrenergic receptors (ßARs), which are essential regulators of mammalian physiology. It has in fact been shown that ßARs interact with estrogen receptors (ER), providing further demonstration of their involvement in determining sexual differences. Based on these premises, this review article focused on the ß3AR subtype, which shows important activities in adipose tissue but with new and interesting roles in regulating the function of cardiomyocytes and vascular cells. In detail, we examined how ß3AR and ER signaling are intertwined and whether there would be sex- and age-dependent specific effects of these receptor systems.
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Envejecimiento , Enfermedades Cardiovasculares , Estrógenos , Receptores Adrenérgicos beta 3 , Receptores de Estrógenos , Humanos , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/fisiopatología , Femenino , Masculino , Receptores Adrenérgicos beta 3/metabolismo , Estrógenos/metabolismo , Receptores de Estrógenos/metabolismo , Envejecimiento/fisiología , Animales , Factores Sexuales , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/fisiopatología , Caracteres Sexuales , Transducción de SeñalRESUMEN
Cancer-associated cachexia (CAC) is a complex multiple organ syndrome that significantly contributes to reduced quality of life and increased mortality among many cancer patients. Its multifactorial nature makes its early diagnosis and effective therapeutic interventions challenging. Adipose tissue is particularly impacted by cachexia, typically through increased lipolysis, browning and thermogenesis, mainly at the onset of the disease. These processes lead to depletion of fat mass and contribute to the dysfunction of other organs. The ß-adrenergic signalling pathways are classical players in the regulation of adipose tissue metabolism. They are activated upon sympathetic stimulation inducing lipolysis, browning and thermogenesis, therefore contributing to energy expenditure. Despite accumulating evidence suggesting that ß3-adrenergic receptor stimulation may be crucial to the adipose tissue remodelling during cachexia, the literature remains controversial. Moreover, there is limited knowledge regarding sexual dimorphism of adipose tissue in the context of cachexia. This review paper aims to present the current knowledge regarding adipose tissue wasting during CAC, with a specific focus on the role of the ß3-adrenergic receptor, placing it as a potential therapeutic target against cachexia.
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Tejido Adiposo , Caquexia , Lipólisis , Neoplasias , Receptores Adrenérgicos beta 3 , Transducción de Señal , Caquexia/metabolismo , Caquexia/patología , Caquexia/etiología , Humanos , Neoplasias/complicaciones , Neoplasias/metabolismo , Neoplasias/patología , Receptores Adrenérgicos beta 3/metabolismo , Tejido Adiposo/metabolismo , Tejido Adiposo/patología , Metabolismo Energético , Termogénesis , AnimalesRESUMEN
Since the first discovery in 1989, the ß3-adrenoceptor (ß3-AR) has gained great attention because it showed the ability to regulate many physiologic and metabolic activities, such as thermogenesis and lipolysis in brown and white adipose tissue, respectively (BAT, WAT), negative inotropic effects in cardiomyocytes, and relaxation of the blood vessels and the urinary bladder. The ß3-AR has been suggested as a potential target for cancer treatment, both in adult and pediatric tumors, since under hypoxia its upregulation in the tumor microenvironment (TME) regulates stromal cell differentiation, tumor growth and metastases, signifying that its agonism/antagonism could be useful for clinical benefits. Promising results in cancer research have proposed the ß3-AR being targeted for the treatment of many conditions, with some drugs, at present, undergoing phase II and III clinical trials. In this review, we report the scientific journey followed by the research from the ß3-Ars' discovery, with focus on the ß3-Ars' role in cancer initiation and progression that elects it an intriguing target for novel antineoplastic approaches. The overview highlights the great potential of the ß3-AR, both in physiologic and pathologic conditions, with the intention to display the possible benefits of ß3-AR modulation in cancer reality.
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Tejido Adiposo Pardo , Neoplasias , Receptores Adrenérgicos beta 3 , Adulto , Niño , Humanos , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/metabolismo , Lipólisis , Receptores Adrenérgicos beta 3/metabolismo , Neoplasias/tratamiento farmacológicoRESUMEN
Preoperative stress has been recognized as an independent risk factor for chronic postsurgical pain (CPSP). However, the underlying mechanisms of CPSP influenced by preoperative stress remain elusive. Previous studies indicated that excessive stress could induce disruption of the blood-spinal cord barrier (BSCB). We wondered whether and how BSCB involves in CPSP by using a single prolonged stress (SPS) combining plantar incision model in male rats to mimic preoperative stress-related postsurgical pain. Here, we observed that preoperative SPS-exposed rats exhibited relentless incisional pain, which was accompanied by impairment of BSCB and persistent elevation of serum IL-6. Intraperitoneal injections of Tocilizumab (an IL-6 receptor monoclonal antibody) not only mitigated BSCB breakdown but also alleviated pain behaviors. In addition, intervening ß3-adrenoceptor (ADRB3) signaling in brown adipocytes by SR59230a (a specific ADRB3 antagonist) treatment or removal of brown adipose tissues could effectively decrease serum IL-6 levels, ameliorate BSCB disruption, and alleviate incisional pain. Further results displayed that SI-exposed rats also showed markedly spinal microglia activation. And exogenous His-tagged IL-6 could pass through the disrupted BSCB, which might contribute to microglia activation. Injection of SR59230a or ablation of brown adipose tissues could effectively reduce the activation of spinal microglia. Thus, our findings suggest that serum IL-6 induced by brown adipocyte ADRB3 signaling contributed to BSCB disruption and spinal microglia activation, which might be involved in preoperative stress mediated CPSP. This work indicates a promising treatment strategy for preoperative stress induced CPSP by blocking ADRB3.
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Adipocitos Marrones , Propanolaminas , Traumatismos de la Médula Espinal , Animales , Masculino , Ratas , Adipocitos Marrones/metabolismo , Interleucina-6/metabolismo , Dolor Postoperatorio , Ratas Sprague-Dawley , Receptores Adrenérgicos/metabolismo , Médula Espinal , Traumatismos de la Médula Espinal/metabolismo , Receptores Adrenérgicos beta 3/metabolismoRESUMEN
Human ß3-adrenoceptor (ß3AR) agonists were considered potential agents for the treatment of metabolic disorders. However, compounds tested as ß3AR ligands have shown marked differences in pharmacological profile in rodent and human species, although these compounds remain attractive as they were successfully repurposed for the therapy of urinary incontinence. In this work, some biarylamine compounds were designed and tested in silico as potential ß3AR agonists on 3-D models of mouse or human ß3ARs. Based on the theoretical results, we identified, synthesized and tested a biarylamine compound (polibegron). In CHO-K1 cells expressing the human ß3AR, polibegron and the ß3AR agonist BRL 37344 were partial agonists for stimulating cAMP accumulation (50 and 57% of the response to isoproterenol, respectively). The potency of polibegron was 1.71- and 4.5-fold higher than that of isoproterenol and BRL37344, respectively. These results indicate that polibegron acts as a potent, but partial, agonist at human ß3ARs. In C57BL/6N mice with obesity induced by a high-fat diet, similar effects of the equimolar intraperitoneal administration of polibegron and BRL37344 were observed on weight, visceral fat and plasma levels of glucose, cholesterol and triglycerides. Similarities and differences between species related to ligand-receptor interactions can be useful for drug designing.
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Agonistas Adrenérgicos beta , Receptores Adrenérgicos beta 3 , Cricetinae , Humanos , Ratones , Animales , Isoproterenol , Receptores Adrenérgicos beta 3/metabolismo , Ratones Endogámicos C57BL , Células CHO , Cricetulus , Agonistas Adrenérgicos beta/farmacologíaRESUMEN
BACKGROUND: The purpose of this study was to evaluate the effects of ß-adrenoceptors (ADRBs) on the urothelial inflammation and zonula occludens (ZO) in a rat PBOO model and in an in vitro model. METHODS: The PBOO model was established by ligating the bladder neck of rats. Twenty rats were divided into 4 groups: sham operation, PBOO + normal saline, PBOO + ADRB2 agonist, PBOO + ADRB3 agonist. PBOO rats were with treated with ADRBs agonists for 3 weeks. Human urothelial cells (HUCs) were subjected to ADRBs agonist treatment or hydrostatic pressure in an in vitro model. RESULTS: In the PBOO group, there was a significant increase in the expression of MCP-1, IL-6 and RANTES compared to the sham group. By contrast, there was a post-PBOO decline in the expression of ZO-1 and ZO-2 in the urothelium. ADRB2 or ADRB3 agonists exhibited downregulated inflammatory cytokine expression and increased ZO expression in the PBOO model. The regulation of inflammation and ZO by ADRB2 and ADRB3 agonists in an in vitro model was found consistent with that in the PBOO model. Moreover, RhoA and ROCK inhibitors suppressed the expression of hydrostatic pressure-induced inflammatory cytokines. Additionally, RhoA agonist reversed the inhibitory effect of ADRBs agonists on the inflammatory secretion from HUCs. CONCLUSIONS: ADRB2 and ADRB3 agonists increased ZO protein expression in HUCs in a rat PBOO model and in an in vitro model. Furthermore, ADRB2 and ADRB3 agonists inhibited the secretion of inflammatory cytokines from HUCs by regulating the RhoA/ROCK signaling pathways.
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Uniones Estrechas , Obstrucción del Cuello de la Vejiga Urinaria , Ratas , Humanos , Animales , Uniones Estrechas/metabolismo , Obstrucción del Cuello de la Vejiga Urinaria/metabolismo , Urotelio/metabolismo , Inflamación/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Receptores Adrenérgicos beta 3/metabolismoRESUMEN
Radix aconiti carmichaeli is a widely used traditional Chinese medicine that has been found to be effective in treating cardiovascular diseases and metabolic disorders. Patients with these diseases often experience a heat generation disorder, which is characterized by chilliness and can worsen the progression of the disease. This study established an in vitro screening model combining the examination of cellular mitochondrial membrane potential and mitochondrial temperature to screen drugs with thermogenic activity. After differentiation and determination of the content of characteristic metabolites of the drug-containing serum blood components, it was found that Fuziline (FZL) is the key thermogenic property in Radix aconiti carmichaeli, responsible for its thermogenic effects with a high relative importance of 33%. Experiments were conducted to evaluate the thermogenic activity of Radix aconiti carmichaeli and FZL in vivo by assessing temperature changes in various organs, including the rectum, liver, and brown adipose tissue. Moreover, the effects of intracellular ß3-adrenergic receptor (ß3-AR) agonistic effects were evaluated using transient ß3-AR transfection and dual-luciferase assay systems. The molecular mechanism by which FZL promotes thermogenesis and improves mitochondrial function was investigated by verifying the ß-adrenergic receptors (ß-AR) downstream signaling pathway. The results suggest that FZL activates ß-AR nonselectively, which in turn activates the downstream cAMP-PKA signaling pathway and leads to an increase in liver glycogenolysis and triglyceride hydrolysis, accompanied by enhancing mitochondrial energy metabolism. Consequently, the liver and brown adipose tissue receive energy to generate heat. In summary, these findings provide insight into the therapeutic application of Radix aconiti carmichaeli for metabolic disorders associated with heat generation disorders.
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Metabolismo de los Lípidos , Receptores Adrenérgicos beta , Humanos , Receptores Adrenérgicos beta/metabolismo , Glucosa/metabolismo , Tejido Adiposo Pardo/metabolismo , Termogénesis , Receptores Adrenérgicos beta 3/metabolismo , Metabolismo EnergéticoRESUMEN
Elevated serum concentrations of glucocorticoids (GCs) result in excessive lipid accumulation in white adipose tissue (WAT) as well as dysfunction of thermogenic brown adipose tissue (BAT), ultimately leading to the development of obesity and metabolic disease. Here, we hypothesized that activation of the sympathetic nervous system either via cold exposure or the use of a selective ß3-adrenergic receptor (ß3-AR) agonist alleviates the adverse metabolic effects of chronic GC exposure in rodents. To this end, male 10-wk-old C57BL/6NRj mice were treated with corticosterone via drinking water or placebo for 4 wk while being maintained at 29°C (thermoneutrality), 22°C (room temperature), or 13°C (cold temperature); in a follow-up study mice received a selective ß3-AR agonist or placebo with and without corticosterone while being maintained at room temperature. Body weight and food intake were monitored throughout the study. Histological and molecular analyses were performed on white and brown adipose depots. Cold exposure not only preserved the thermogenic function of brown adipose tissue but also reversed GC-induced lipid accumulation in white adipose tissue and corrected GC-driven obesity, hyperinsulinemia, and hyperglycemia. The metabolic benefits of cold exposure were associated with enhanced sympathetic activity in adipose tissue, thus potentially linking an increase in sympathetic signaling to the observed metabolic benefits. In line with this concept, chronic administration of a selective ß3-AR agonist reproduced the beneficial metabolic effects of cold adaption during exposure to exogenous GCs. This preclinical study demonstrates the potential of ß3-AR as a therapeutic target in the management and prevention of GC-induced metabolic disease.NEW & NOTEWORTHY This preclinical study in mice shows that the ß3-adrenergic receptor can be a potential therapeutic approach to counteracting glucocorticoid (GC)-induced obesity and metabolic dysfunction. Both cold acclimation and ß3-adrenergic receptor stimulation in a mouse model of excess glucocorticoids were adequate in not only preventing obesity, adiposity, and adipose tissue dysfunction but also correcting hyperinsulinemia, hyperleptinemia, and dyslipidemia.
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Glucocorticoides , Receptores Adrenérgicos beta , Masculino , Animales , Ratones , Glucocorticoides/farmacología , Glucocorticoides/metabolismo , Receptores Adrenérgicos beta/metabolismo , Corticosterona/metabolismo , Estudios de Seguimiento , Ratones Endogámicos C57BL , Tejido Adiposo/metabolismo , Obesidad/inducido químicamente , Obesidad/metabolismo , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Lípidos , TermogénesisRESUMEN
Neuroblastoma (NB) is a heterogeneous extracranial tumor occurring in childhood. A distinctive feature of NB tumors is their neuroendocrine ability to secrete catecholamines, which in turn, via ß-adrenergic receptors ligation, may affect different signaling pathways in tumor microenvironment (TME). It was previously demonstrated that specific antagonism of ß3-adrenergic receptor (ß3-AR) on NB tumor cells affected tumor growth and progression. Here, in a murine syngeneic model of NB, we aimed to investigate whether the ß3-AR modulation influenced the host immune system response against tumor. Results demonstrated that ß3-AR antagonism lead to an immune response reactivation, partially dependent on the PD-1/PD-L1 signaling axis involvement. Indeed, ß3-AR blockade on tumor-infiltrating lymphocytes (TILs) dampened their ability to secrete IFN-γ, which in turn reduced the PD-L1 expression, caused by TILs infiltration, on NB tumor cells. Further investigations, through a genomic analysis on NB patients, showed that high ADRB3 gene expression correlates with worse clinical outcome compared to the low expression group, and that ADRB3 gene expression affects different immune-related pathways. Overall, results indicate that ß3-AR in NB TME is able to modulate the interaction between tumor and host immune system, and that its antagonism hits multiple pro-tumoral signaling pathways.
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Interferón gamma , Neuroblastoma , Humanos , Animales , Ratones , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Linfocitos Infiltrantes de Tumor , Neuroblastoma/genética , Receptores Adrenérgicos beta 3/genética , Receptores Adrenérgicos beta 3/metabolismo , Microambiente TumoralRESUMEN
In the retina, hypoxic condition leads to overgrowing leaky vessels resulting in altered metabolic supply that may cause impaired visual function. Hypoxia-inducible factor-1 (HIF-1) is a central regulator of the retinal response to hypoxia by activating the transcription of numerous target genes, including vascular endothelium growth factor, which acts as a major player in retinal angiogenesis. In the present review, oxygen urge by the retina and its oxygen sensing systems including HIF-1 are discussed in respect to the role of the beta-adrenergic receptors (ß-ARs) and their pharmacologic manipulation in the vascular response to hypoxia. In the ß-AR family, ß1- and ß2-AR have long been attracting attention because their pharmacology is intensely used for human health, while ß3-AR, the third and last cloned receptor is no longer increasingly emerging as an attractive target for drug discovery. Here, ß3-AR, a main character in several organs including the heart, the adipose tissue and the urinary bladder, but so far a supporting actor in the retina, has been thoroughly examined in respect to its function in retinal response to hypoxia. In particular, its oxygen dependence has been taken as a key indicator of ß3-AR involvement in HIF-1-mediated responses to oxygen. Hence, the possibility of ß3-AR transcription by HIF-1 has been discussed from early circumstantial evidence to the recent demonstration that ß3-AR acts as a novel HIF-1 target gene by playing like a putative intermediary between oxygen levels and retinal vessel proliferation. Thus, targeting ß3-AR may implement the therapeutic armamentarium against neovascular pathologies of the eye.
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Receptores Adrenérgicos beta , Neovascularización Retiniana , Humanos , Receptores Adrenérgicos beta/metabolismo , Neovascularización Retiniana/metabolismo , Retina/metabolismo , Oxígeno/metabolismo , Hipoxia/metabolismo , Receptores Adrenérgicos beta 3/metabolismoRESUMEN
Cancer is the leading cause of death and represents a significant economic burden worldwide. The numbers are constantly growing as a result of increasing life expectancy, toxic environmental factors, and adoption of Western lifestyle. Among lifestyle factors, stress and the related signaling pathways have recently been implicated in the development of tumors. Here we present some epidemiological and preclinical data concerning stress-related activation of the ß-adrenoreceptors (ß-ARs), which contributes to the formation, sequential transformation, and migration of different tumor cell types. We focused our survey on research results for breast and lung cancer, melanoma, and gliomas published in the past five years. Based on the converging evidence, we present a conceptual framework of how cancer cells hijack a physiological mechanism involving ß-ARs toward a positive modulation of their own survival. In addition, we also highlight the potential contribution of ß-AR activation to tumorigenesis and metastasis formation. Finally, we outline the antitumor effects of targeting the ß-adrenergic signaling pathways, methods for which primarily include repurposed ß-blocker drugs. However, we also call attention to the emerging (though as yet largely explorative) method of chemogenetics, which has a great potential in suppressing tumor growth either by selectively modulating neuronal cell groups involved in stress responses affecting cancer cells or by directly manipulating specific (e.g., the ß-AR) receptors on a tumor and its microenvironment.
Asunto(s)
Melanoma , Humanos , Melanoma/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Transducción de Señal , Microambiente TumoralRESUMEN
Objective: The objective of this study was to functionally analyze the correlation of key histological features in brown adipose tissue (BAT) with clinical metabolic traits in nonhuman primates. Methods: Axillary adipose tissue biopsies were collected from a metabolically diverse nonhuman primate cohort with clinical metabolism-related data. Expression of tyrosine hydroxylase (TH), uncoupling protein 1 (UCP1), cluster of differentiation 31 (CD31), cytochrome c oxidase subunit 4 (COX IV), beta-3 adrenergic receptor (ß3-AR), and adipose cell size were quantified by immunohistochemical analysis. Computed tomography scans were performed to assess body composition. Results: Tyrosine hydroxylase was negatively correlated with whole body fat mass as a percentage of body weight (p = 0.004) and was positively correlated with the density of UCP1 (p = 0.02), COX IV (p = 0.006), CD31 (p = 0.007), and cell density (p = 0.02) of the BAT samples. Beta-3 adrenergic receptor abundance had a weak positive correlation with COX IV (p = 0.04) in BAT but did not significantly correlate to UCP1 or TH expression in BAT. Conclusions: Our findings highlight that there is a disparity in innervation provided to BAT based on body composition, as seen with the negative association between TH, a marker for innervation, and adiposity. These findings also support the importance of innervation in the functionality of BAT, as TH abundance not only supports leaner body composition but is also positively correlated with known structural elements in BAT (UCP1, COX IV, CD31, and cell density). Based on our observations, ß3-AR abundance does not strongly drive these structural elements or TH, all of which are known to be important in the function of brown adipose tissue. In effect, while the role of other receptors, such as ß2-AR, should be reviewed in BAT function, these results support the development of safe sympathetic nervous system stimulants to activate brown adipose tissue for obesity treatment.
Asunto(s)
Tejido Adiposo Pardo , Receptores Adrenérgicos beta 3 , Animales , Tejido Adiposo Pardo/inervación , Primates/metabolismo , Receptores Adrenérgicos beta 3/metabolismo , Termogénesis/fisiología , Tirosina 3-Monooxigenasa/metabolismo , Tirosina 3-Monooxigenasa/farmacología , Proteína Desacopladora 1/metabolismoRESUMEN
AIMS: ß3 -adrenoceptors (ARs) are an important drug target for the treatment of overactive bladder syndrome (OAB) and are under investigation for other indications. The human ß3 -AR gene is polymorphic; an exchange of amino acid tryptophan (Trp) for arginine (Arg) in position 64 of the receptor protein is the most frequent and best-studied polymorphism. A narrative review on the impact of ß3 -AR polymorphisms on urological disease and its treatment is presented. RESULTS: Two out of four studies have reported that the 64Arg allele was found more frequently in subjects with OAB than in healthy controls. A large study in a highly selective population (men undergoing prostatectomy for cancer treatment) did not confirm this. On the other hand, studies examining symptom severity typically found little difference between 64Arg and 64Trp carriers. In vitro studies with endogenously expressed ß3 -AR reported a decreased lipolytic response in human adipose tissue. Studies with heterologously expressed receptors sometimes found a decreased responsiveness to agonists including ß3 -AR agonists, but others did not confirm that. CONCLUSIONS: The overall evidence points to carriers of the 64Arg genotype expressing fewer and/or hypofunctional ß3 -ARs and being associated with the presence of OAB but such findings were only detected inconsistently. If this hypofunctionality exists, the consequences may be of insufficient magnitude to allow a robust detection. Only adequately powered studies comparing responses with a ß3 -AR agonist in 64Arg carriers versus wild-type patients can address this.
Asunto(s)
Vejiga Urinaria Hiperactiva , Urología , Masculino , Humanos , Receptores Adrenérgicos beta 3/genética , Receptores Adrenérgicos beta 3/metabolismo , Polimorfismo Genético , Genotipo , Agonistas de Receptores Adrenérgicos beta 3/uso terapéuticoRESUMEN
We aimed to investigate the efficacy of exercise on preventing arterial stiffness and the potential role of sympathetic nerves within perivascular adipose tissue (PVAT) in pressure-overload-induced heart failure (HF) mice. Eight-week-old male mice were subjected to sham operation (SHAM), transverse aortic constriction-sedentary (TAC-SE), and transverse aortic constriction-exercise (TAC-EX) groups. Six weeks of aerobic exercise training was performed using a treadmill. Arterial stiffness was determined by measuring the elastic modulus. The elastic and collagen fibers of the aorta and sympathetic nerve distribution in PVAT were observed. Circulating noradrenaline (NE), expressions of ß3-adrenergic receptor (ß3-AR), and adiponectin in PVAT were quantified. During the recovery of cardiac function by aerobic exercise, thoracic aortic collagen elastic modulus (CEM) and collagen fibers were significantly decreased (p < 0.05, TAC-SE vs. TAC-EX), and elastin elastic modulus (EEM) was significantly increased (p < 0.05, TAC-SE vs. TAC-EX). Circulating NE and sympathetic nerve distribution in PVAT were significantly decreased (p < 0.05, TAC-SE vs. TAC-EX). The expression of ß3-AR was significantly reduced (p < 0.05, TAC-SE vs. TAC-EX), and adiponectin was significantly increased (p < 0.05, TAC-SE vs. TAC-EX) in PVAT. Regular aerobic exercise can effectively prevent arterial stiffness and extracellular matrix (ECM) remodeling in the developmental course of HF, during which sympathetic innervation and adiponectin within PVAT might be strongly implicated.