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Obesity (Silver Spring, Md.) Jul 2015Mice are typically housed at environmental temperatures below thermoneutrality, whereas humans live near thermoneutrality. This difference affects energy physiology and,... (Comparative Study)
Comparative Study
OBJECTIVE
Mice are typically housed at environmental temperatures below thermoneutrality, whereas humans live near thermoneutrality. This difference affects energy physiology and, potentially, anti-obesity drug efficacy. Here β3-adrenergic agonist treatment at thermoneutrality (30°C) versus room temperature (22°C) is compared.
METHODS
Male C57BL/6J mice were singly housed at 30°C or 22°C and treated with vehicle or CL316243, a β3-agonist, for 4 weeks. Food intake, energy expenditure, body and adipose weight, brown adipose activity, white adipose browning, and glucose tolerance were evaluated. CL316243 treatment was studied in both chow- and high-fat diet-fed mice.
RESULTS
Mice at 30°C, compared to 22°C, had reduced food intake, metabolic rate, and brown adipose activity, as well as increased adiposity. At both temperatures, CL316243 treatment increased brown adipose activation and energy expenditure and improved glucose tolerance. At 30°C, CL316243 increased energy expenditure disproportionately to changes in food intake, thus reducing adiposity, while at 22°C these changes were matched, yielding unchanged adiposity.
CONCLUSIONS
CL316243 treatment can have beneficial metabolic effects in the absence of adiposity changes. In addition, the interaction between environmental temperature and CL316243 treatment is different from the interaction between environmental temperature and 2,4-dinitrophenol treatment reported previously, suggesting that each drug mechanism must be examined to understand the effect of environmental temperature on drug efficacy.
Topics: Adipose Tissue; Adrenergic Agonists; Adrenergic beta-3 Receptor Agonists; Animals; Anti-Obesity Agents; Body Weight; Dioxoles; Eating; Energy Metabolism; Male; Mice; Mice, Inbred C57BL; Obesity; Temperature; Thermogenesis; Weight Loss
PubMed: 26053335
DOI: 10.1002/oby.21124 -
Journal of the National Medical... Feb 2021Outcome differences driven by variation in Blacks' biologic response to treatment may contribute to persistent racial disparities in asthma morbidity and mortality. This... (Review)
Review
PURPOSE
Outcome differences driven by variation in Blacks' biologic response to treatment may contribute to persistent racial disparities in asthma morbidity and mortality. This review assessed systematic variation in β agonist treatment outcomes among Blacks compared to other groups.
METHODS
We conducted a systematic review of studies reporting differential response to β agonists among Blacks, including studies identifying pharmacogenetic variants.
RESULTS
Of 3158 papers, 20 compared safety or efficacy of β agonists among Blacks as compared with other subgroups. Six papers evaluating efficacy of short-acting β agonists (SABA) found similar or improved results among Blacks compared with other groups, while one small study found reduced response to SABA therapy among Blacks. Reports of safety and efficacy of long-acting β agonists (LABA) indicated similar results among Blacks in four papers, while four reports found reduced safety among Blacks, as compared with other groups. Four papers assessed genomic variation and relative treatment response in Blacks, with two finding significant effects of the p.Arg16Gly variant in ADRB2 on β agonist response and one finding significant gene-gene IL6/IL6R interaction effects on albuterol response.
CONCLUSIONS
Evidence suggests the potential for differences in β agonist outcomes among Blacks compared with other groups. This literature, however, remains small and significantly underpowered for substantive conclusions. There are notable opportunities for adequately-powered investigations exploring safety and efficacy of β agonists among Blacks, including pharmacogenomic modifiers of response.
Topics: Administration, Inhalation; Adrenergic Agonists; Black or African American; Asthma; Drug Therapy, Combination; Humans
PubMed: 32732018
DOI: 10.1016/j.jnma.2020.07.001 -
Obesity (Silver Spring, Md.) Jan 2022Beta-3 adrenergic receptors (β3-AR) stimulate lipolysis and thermogenesis in white and brown adipose tissue (WAT and BAT). Obesity increases oxidative stress and...
OBJECTIVES
Beta-3 adrenergic receptors (β3-AR) stimulate lipolysis and thermogenesis in white and brown adipose tissue (WAT and BAT). Obesity increases oxidative stress and inflammation that attenuate AT β3-AR signaling. The objective of this study was to test the hypothesis that the combination of the β3-AR agonist CL-316,243 (CL) and the antioxidant alpha-lipoic acid (ALA) would lower inflammation in diet-induced obesity (DIO) and improve β3-AR function.
METHODS
A total of 40 DIO mice were separated into four groups: Control (per os and intraperitoneal [IP] vehicle); CL alone (0.01 mg/kg IP daily); ALA alone (250 mg/kg in drinking water); or ALA+CL combination, all for 5 weeks.
RESULTS
Food intake was similar in all groups; however, mice receiving ALA+CL showed improved body composition and inflammation as well as lower body weight (+1.7 g Control vs. -2.5 g ALA+CL [-7%]; p < 0.01) and percentage of body fat (-9%, p < 0.001). Systemic and epididymal WAT inflammation was lower with ALA+CL than all other groups, with enhanced recruitment of epididymal WAT anti-inflammatory CD206+ M2 macrophages. β3-AR signaling in WAT was enhanced in the combination-treatment group, with higher mRNA and protein levels of thermogenic uncoupling protein 1 and AT lipases.
CONCLUSIONS
Chronic treatment with ALA and a β3-AR agonist reduces DIO-induced inflammation. AT immune modulation could be a therapeutic target in patients with obesity.
Topics: Adipose Tissue, Brown; Adrenergic Agonists; Animals; Diet, High-Fat; Humans; Inflammation; Male; Mice; Mice, Obese; Obesity; Thioctic Acid
PubMed: 34825496
DOI: 10.1002/oby.23309 -
Journal of Shoulder and Elbow Surgery Feb 2021Rotator cuff (RC) muscle atrophy and fatty infiltration (FI) are independent factors correlated with failure of attempted tendon repair in larger RC tears. However,...
BACKGROUND
Rotator cuff (RC) muscle atrophy and fatty infiltration (FI) are independent factors correlated with failure of attempted tendon repair in larger RC tears. However, there is no effective treatment for RC muscle atrophy and FI at this time. The recent discovery of beige adipose tissue (BAT) in adults shed light on a new avenue in treating obesity and excessive fat deposition by promoting BAT activity. The goal of this study was to define the role of intramuscular BAT in RC muscle FI and the effect of β-adrenergic receptor agonists in treating RC muscle FI by promoting BAT activity.
MATERIALS AND METHODS
Three-month-old wild-type C57BL/6J, platelet derived growth factor receptor-alpha (PDGFRα) green fluorescent protein (GFP) reporter and uncoupling protein 1 (UCP-1) knockout mice underwent a unilateral RC injury procedure, which included supraspinatus (SS) and infraspinatus tendon resection and suprascapular nerve transection. To stimulate BAT activity, amibegron, a selective β-adrenergic receptor agonist, was administered to C57BL/6J mice either on the same day as surgery or 6 weeks after surgery through daily intraperitoneal injections. Gait analysis was conducted to measure forelimb function at 6 weeks or 12 weeks (in groups receiving delayed amibegron treatment) after surgery. Animals were killed humanely at 6 weeks (or 12 weeks for delayed amibegron groups) after surgery. SS muscles were harvested and analyzed histologically and biochemically.
RESULTS
Histologic analysis of SS muscles from PDGFRα-GFP reporter mice showed that PDGFRα-positive fibroadipogenic progenitors in RC muscle expressed UCP-1, a hallmark of BAT during the development of FI after RC tears. Impairing BAT activity by knocking out UCP-1 resulted in more severe muscle atrophy and FI with inferior forelimb function in UCP-1 knockout mice compared with wild-type mice. Promoting BAT activity with amibegron significantly reduced muscle atrophy and FI after RC tears and improved forelimb function. Delayed treatment with amibegron reversed muscle atrophy and FI in muscle.
CONCLUSIONS
Fat accumulated in muscle after RC tears possesses BAT characteristics. Impairing BAT activity results in worse RC muscle atrophy and FI. Amibegron reduces and reverses RC atrophy and FI by promoting BAT activity.
Topics: Adipose Tissue; Adipose Tissue, Beige; Adrenergic Agonists; Animals; Mice; Mice, Inbred C57BL; Muscular Atrophy; Rotator Cuff; Rotator Cuff Injuries
PubMed: 32599287
DOI: 10.1016/j.jse.2020.06.006 -
Revista Brasileira de Terapia Intensiva 2021Cardiac, ventilatory and kidney management in the critical care setting has been optimized over the past decades. Cognition and sedation represent one of the last...
Cardiac, ventilatory and kidney management in the critical care setting has been optimized over the past decades. Cognition and sedation represent one of the last remaning challenges. As conventional sedation is suboptimal and as the sedation evoked by alpha-2 adrenergic agonists ("cooperative" sedation with dexmedetomidine, clonidine or guanfacine) represents a valuable alternative, this manuscript covers three practical topics for which evidence-based medicine is lacking: a) Switching from conventional to cooperative sedation ("switching"): the short answer is the abrupt withdrawal of conventional sedation, immediate implementation of alpha-2 agonist infusion and the use of "rescue sedation" (midazolam bolus[es]) or "breakthrough sedation" (haloperidol bolus[es]) to stabilize cooperative sedation. b) Switching from conventional to cooperative sedation in unstable patients (e.g., refractory delirium tremens, septic shock, acute respiratory distress syndrome, etc.): to avoid hypotension and bradycardia evoked by sympathetic deactivation, the short answer is to maintain the stroke volume through volume loading, vasopressors and inotropes. c) To avoid these switches and associated difficulties, alpha-2 agonists may be considered first-line sedatives. The short answer is to administer alpha-2 agonists slowly from admission or endotracheal intubation up to stabilized cooperative sedation. The "take home" message is as follows: a) alpha-2 agonists are jointly sympathetic deactivators and sedative agents; b) sympathetic deactivation implies maintaining the stroke volume and iterative assessment of volemia. Evidence-based medicine should document our propositions.
Topics: Adrenergic alpha-2 Receptor Agonists; Clonidine; Critical Care; Dexmedetomidine; Humans; Hypnotics and Sedatives
PubMed: 35081245
DOI: 10.5935/0103-507X.20210087 -
Biomolecules Dec 2023Oxygen level is a key regulator of organogenesis and its modification in postnatal life alters the maturation process of organs, including the intestine, which do not...
Oxygen level is a key regulator of organogenesis and its modification in postnatal life alters the maturation process of organs, including the intestine, which do not completely develop in utero. The β3-adrenoreceptor (β3-AR) is expressed in the colon and has an oxygen-dependent regulatory mechanism. This study shows the effects of the β3-AR agonist BRL37344 in a neonatal model of hyperoxia-driven colonic injury. For the first 14 days after birth, Sprague-Dawley rat pups were exposed to ambient oxygen levels (21%) or hyperoxia (85%) and treated daily with BRL37344 at 1, 3, 6 mg/kg or untreated. At the end of day 14, proximal colon samples were collected for analysis. Hyperoxia deeply influences the proximal colon development by reducing β3-AR-expressing cells (27%), colonic length (26%) and mucin production (47%), and altering the neuronal chemical coding in the myenteric plexus without changes in the neuron number. The administration of BRL37344 at 3 mg/kg, but not at 1 mg/kg, significantly prevented these alterations. Conversely, it was ineffective in preventing hyperoxia-induced body weight loss. BRL37344 at 6 mg/kg was toxic. These findings pave the way for β3-AR pharmacological targeting as a therapeutic option for diseases caused by hyperoxia-impaired development, typical prematurity disorders.
Topics: Rats; Animals; Ethanolamines; Hyperoxia; Rats, Sprague-Dawley; Adrenergic Agonists; Receptors, Adrenergic, beta-3; Oxygen
PubMed: 38136626
DOI: 10.3390/biom13121755 -
British Journal of Pharmacology Nov 2018The β -adrenoceptor was initially an attractive target for several pharmaceutical companies due to its high expression in rodent adipose tissue, where its activation... (Review)
Review
UNLABELLED
The β -adrenoceptor was initially an attractive target for several pharmaceutical companies due to its high expression in rodent adipose tissue, where its activation resulted in decreased adiposity and improved metabolic outputs (such as glucose handling) in animal models of obesity and Type 2 diabetes. However, several drugs acting at the β -adrenoceptor failed in clinical trials. This was thought to be due to their lack of efficacy at the human receptor. Recently, mirabegron, a β -adrenoceptor agonist with human efficacy, was approved in North America, Europe, Japan and Australia for the treatment of overactive bladder syndrome. There are indications that mirabegron may act at other receptors/targets, but whether they have any clinical relevance is relatively unknown. Besides overactive bladder syndrome, mirabegron may have other uses such as in the treatment of heart failure or metabolic disease. This review gives an overview of the off-target effects of mirabegron and its potential use in the treatment of other diseases.
LINKED ARTICLES
This article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.21/issuetoc.
Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Animals; Humans; Receptors, Adrenergic, beta-3; Thiazoles; Urinary Bladder
PubMed: 29243229
DOI: 10.1111/bph.14121 -
Advanced Science (Weinheim,... Dec 2023Mirabegron, commonly known as "Myrbetriq", has been widely prescribed as a medicine for overactive bladder syndrome for over a decade. However, the structure of the drug...
Mirabegron, commonly known as "Myrbetriq", has been widely prescribed as a medicine for overactive bladder syndrome for over a decade. However, the structure of the drug and what conformational changes it may undergo upon binding its receptor remain unknown. In this study, the authors employed microcrystal electron diffraction (MicroED) to reveal its elusive three-dimensional (3D) structure. They find that the drug adopts two distinct conformational states (conformers) within the asymmetric unit. Analysis of hydrogen bonding and packing demonstrated that the hydrophilic groups are embedded within the crystal lattice, resulting in a hydrophobic surface and low water solubility. Structural comparison revealed the presence of trans- and cis- forms in conformers 1 and 2, respectively. Comparison of the structures of Mirabegron alone with that of the drug bound to its receptor, the beta 3 adrenergic receptor (β3AR) suggests that the drug undergoes major conformational change to fit in the receptor agonist binding site. This research highlights the efficacy of MicroED in determining the unknown and polymorphic structures of active pharmaceutical ingredients (APIs) directly from powders.
Topics: Humans; Urinary Bladder, Overactive; Electrons; Adrenergic beta-3 Receptor Agonists; Acetanilides
PubMed: 37847906
DOI: 10.1002/advs.202304476 -
Drug News & Perspectives Apr 2007Alpha2-adrenergic receptor agonists exert potent analgesic and sedative/hypnotic effects. In addition, they have been shown to be neuroprotective in various experimental... (Review)
Review
Alpha2-adrenergic receptor agonists exert potent analgesic and sedative/hypnotic effects. In addition, they have been shown to be neuroprotective in various experimental models, but the molecular pathways leading to these actions are still poorly defined. This review summarizes the available literature and discusses potential mechanisms of alpha2-adrenergic receptor agonist mediated neuroprotection.
Topics: Adrenergic Agonists; Adrenergic alpha-2 Receptor Agonists; Animals; Humans; Imidazolines; Neuroprotective Agents
PubMed: 17520091
DOI: 10.1358/dnp.2007.20.3.1084644 -
British Journal of Pharmacology Sep 2009It has been demonstrated that the degree of agonist-induced desensitization of the beta(2)-adrenoceptor is related to agonist efficacy (strength of signalling), whereby... (Review)
Review
It has been demonstrated that the degree of agonist-induced desensitization of the beta(2)-adrenoceptor is related to agonist efficacy (strength of signalling), whereby high-efficacy agonists (e.g. formoterol) cause more phosphorylation and internalization of the receptor than low-efficacy agonists (e.g. salmeterol). These early studies, however, used a protocol where agonists were matched for receptor occupancy rather than functional effect. In this issue of the BJP, Duringer and colleagues have extended these studies to compare the ability of agonists to cause desensitization at equi-effective (cAMP signalling) concentrations rather than equal occupancy. Their data and conclusions are quite different from those previously described. After prolonged exposure, all the agonists caused a similar degree of desensitization, whereas a pulse protocol uncovered a greater loss of responsiveness with the low-efficacy ligands. This is consistent with the notion that high-efficacy agonists have 'spare receptors', and are therefore less sensitive to loss of receptors through desensitization. It also reflects experience in the clinic, where both formoterol and salmeterol show a similar early decline in bronchoprotection, after which their effects remain stable. These findings challenge the notion that high-efficacy ligands always cause more functional desensitization.
Topics: Adrenergic Agonists; Adrenergic beta-2 Receptor Agonists; Animals; Humans; Receptors, Adrenergic, beta-2
PubMed: 19719779
DOI: 10.1111/j.1476-5381.2009.00352.x