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Contrast Media & Molecular Imaging 2022Browning of white adipose tissue (WAT) into beige adipocytes has been proposed as a strategy to tackle the ongoing obesity epidemic. Thermogenic stimuli have been...
Browning of white adipose tissue (WAT) into beige adipocytes has been proposed as a strategy to tackle the ongoing obesity epidemic. Thermogenic stimuli have been investigated with the aim of converting existing white adipose tissue, primarily used for energy storage, into beige adipocytes capable of dissipating energy; however, evaluation is complicated by the dearth of noninvasive methodologies to quantify beige adipocytes in WAT. Imaging with [F]FDG is commonly used to measure brown adipose tissue (BAT) and beige adipocytes but the relationship between beige adipocytes, thermogenesis and [F]FDG uptake is unclear. [F]BCPP-EF, a tracer for mitochondrial complex-I (MC-I), acts as a marker of oxidative metabolism and may be useful for the detection of newly formed beige adipocytes. Mice received doses of the 3-adrenergic agonist CL-316,243 subchronically for 7 days to induce formation of beige adipocytes in inguinal white fat. PET imaging was performed longitudinally with both [F]FDG (a marker of glycolysis) and [F]BCPP-EF (an MC-I marker) to assess the effect of thermogenic stimulation on uptake in browning inguinal WAT and interscapular BAT. Treatment with CL-316,243 led to significant increases in both [F]FDG and [F]BCPP-EF in inguinal WAT. The uptake of [F]BCPP-EF in inguinal WAT was significantly increased above control levels after 3 days of stimulation, whereas [F]FDG only showed a significant increase after 7 days. The uptake of [F]BCPP-EF in newly formed beige adipocytes was blocked by pretreatment with an adrenoceptor antagonist suggesting that beige adipocyte formation may be associated with the activation of MC-I. However, in BAT, uptake of [F]BCPP-EF was unaffected by 3-adrenergic stimulation, potentially due to the high expression of MC-I. [F]BCPP-EF can detect newly formed beige adipocytes in WAT generated after subchronic treatment with the 3-adrenergic agonist CL-316,243 and displays both higher inguinal WAT uptake and earlier detection than [F]FDG. The MC-I tracer may be a useful tool in the evaluation of new therapeutic strategies targeting metabolic adipose tissues to tackle obesity and metabolic diseases.
Topics: Adipose Tissue, Brown; Adrenergic Agonists; Animals; Fluorodeoxyglucose F18; Mice; Obesity; Positron-Emission Tomography
PubMed: 35694709
DOI: 10.1155/2022/6113660 -
Respirology (Carlton, Vic.) Sep 2023Raised blood lactate secondary to high dose β -agonist treatment has been reported in asthma exacerbations but has not been investigated during acute exacerbations of...
BACKGROUND AND OBJECTIVE
Raised blood lactate secondary to high dose β -agonist treatment has been reported in asthma exacerbations but has not been investigated during acute exacerbations of COPD (AECOPD). We explored associations of blood lactate measurements with disease outcomes and β -agonist treatments during AECOPD.
METHODS
Retrospective (n = 199) and prospective studies (n = 142) of patients hospitalized with AECOPD were conducted. The retrospective cohort was identified via medical records and the prospective cohort was recruited during hospitalization for AECOPD. Baseline demographics, comorbidities, β -agonist treatment, biochemical measurements and clinical outcomes were compared between patients with normal (≤2.0 mmol/L) versus elevated lactate (>2.0 mmol/L). Regression analyses examined associations of lactate measurements with β -agonist dosages.
RESULTS
Demographic data and comorbidities were similar between high versus normal lactate groups in both cohorts. The populations were elderly (mean >70 years), predominantly male (>60%) with reduced FEV (%) 48.2 ± 19 (prospective cohort). Lactate was elevated in approximately 50% of patients during AECOPD and not related to evidence of sepsis. In the prospective cohort, patients with high lactate had more tachypnoea, tachycardia, acidosis and hyperglycaemia (p < 0.05) and received more non-invasive ventilation (37% vs. 9.7%, p < 0.001, prospective cohort). There was a trend to longer hospitalization (6 vs. 5 days, p = 0.06, prospective cohort). Higher cumulative β -agonist dosages were linked to elevated lactate levels (OR 1.04, p = 0.01).
CONCLUSION
Elevated lactate during AECOPD was common, unrelated to sepsis and correlated with high cumulative doses of β -agonists. Raised lactate may indicate excessive β -agonist treatment and should now be investigated as a possible biomarker.
Topics: Humans; Male; Aged; Female; Adrenergic beta-2 Receptor Agonists; Prospective Studies; Retrospective Studies; Pulmonary Disease, Chronic Obstructive; Lactates
PubMed: 37400102
DOI: 10.1111/resp.14534 -
Human Immunology Oct 2023T helper 17 (Th17) cells produce IL-17A cytokine and can exacerbate autoimmune diseases and asthma. The β2 adrenergic receptor is a g protein-coupled receptor that...
BACKGROUND
T helper 17 (Th17) cells produce IL-17A cytokine and can exacerbate autoimmune diseases and asthma. The β2 adrenergic receptor is a g protein-coupled receptor that induces cAMP second messenger pathways. We tested the hypothesis that terbutaline, a β2-adrenergic receptor-specific agonist, promotes IL-17 secretion by memory Th17 cells in a cAMP and PKA-dependent manner.
METHODS
Venous peripheral blood mononuclear cells (PBMC) from healthy human participants were activated with anti-CD3 and anti-CD28 antibodies. Secreted IL-17A was measured by enzyme linked immunosorbent assay, intracellular IL-17A, and RORγ were measured using flow cytometry, and RORC by qPCR. Memory CD3CD4CD45RACD45RO T cells were obtained by immunomagnetic negative selection and activated with tri-antibody complex CD3/CD28/CD2. Secreted IL-17A, intracellular IL-17A, RORC were measured, and phosphorylated-serine133-CREB was measured by western blotting memory Th cells.
RESULTS
Terbutaline increased IL-17A (p < 0.001), IL-17A cells (p < 0.05), and RORC in activated PBMC and memory Th cells. The PKA inhibitors H89 (p < 0.001) and Rp-cAMP (p < 0.01) abrogated the effects of terbutaline on IL-17A secretion in PBMC and memory T cells. Rolipram increased IL-17A (p < 0.01) to a similar extent as terbutaline. P-Ser133-CREB was increased by terbutaline (p < 0.05) in memory T cells.
CONCLUSION
Terbutaline augments memory Th17 cells in lymphocytes from healthy participants. This could exacerbate autoimmune diseases or asthma, in cases where Th17 cells are considered to be pro-inflammatory.
Topics: Humans; Adrenergic Agonists; Asthma; Autoimmune Diseases; CD28 Antigens; Cyclic AMP-Dependent Protein Kinases; Interleukin-17; Leukocytes, Mononuclear; Receptors, Adrenergic; Terbutaline; Th17 Cells
PubMed: 37438188
DOI: 10.1016/j.humimm.2023.06.007 -
Cell Stem Cell Sep 2019Hematopoietic stem cells (HSCs) residing in the bone marrow (BM) accumulate during aging but are functionally impaired. However, the role of HSC-intrinsic and -extrinsic...
Hematopoietic stem cells (HSCs) residing in the bone marrow (BM) accumulate during aging but are functionally impaired. However, the role of HSC-intrinsic and -extrinsic aging mechanisms remains debated. Megakaryocytes promote quiescence of neighboring HSCs. Nonetheless, whether megakaryocyte-HSC interactions change during pathological/natural aging is unclear. Premature aging in Hutchinson-Gilford progeria syndrome recapitulates physiological aging features, but whether these arise from altered stem or niche cells is unknown. Here, we show that the BM microenvironment promotes myelopoiesis in premature/physiological aging. During physiological aging, HSC-supporting niches decrease near bone but expand further from bone. Increased BM noradrenergic innervation promotes β-adrenergic-receptor(AR)-interleukin-6-dependent megakaryopoiesis. Reduced β-AR-Nos1 activity correlates with decreased endosteal niches and megakaryocyte apposition to sinusoids. However, chronic treatment of progeroid mice with β-AR agonist decreases premature myeloid and HSC expansion and restores the proximal association of HSCs to megakaryocytes. Therefore, normal/premature aging of BM niches promotes myeloid expansion and can be improved by targeting the microenvironment.
Topics: Adrenergic Agonists; Aging; Aging, Premature; Animals; Bone Marrow; Cell Differentiation; Cell Encapsulation; Cell Proliferation; Disease Models, Animal; Hematopoietic Stem Cells; Humans; Interleukin-6; Megakaryocytes; Mice; Myeloid Cells; Nitric Oxide Synthase Type I; Progeria; Receptors, Adrenergic, beta-2; Signal Transduction; Stem Cell Niche
PubMed: 31303548
DOI: 10.1016/j.stem.2019.06.007 -
ACS Chemical Neuroscience Nov 2019Agonists at the α adrenergic receptor produce sedation, increase focus, provide analgesia, and induce centrally mediated hypotension and bradycardia, yet neither their...
Agonists at the α adrenergic receptor produce sedation, increase focus, provide analgesia, and induce centrally mediated hypotension and bradycardia, yet neither their dynamic interactions with adrenergic receptors nor their modulation of neuronal circuit activity is completely understood. Photoaffinity ligands of α adrenergic agonists have the potential both to capture discrete moments of ligand-receptor interactions and to prolong naturalistic drug effects in discrete regions of tissue in vivo. We present here the synthesis and characterization of a novel α adrenergic agonist photolabel based on the imidazole medetomidine called . Azi-medetomidine shares protein association characteristics with its parent compound in experimental model systems and by molecular dynamics simulation of interactions with the α adrenergic receptor. Azi-medetomidine acts as an agonist at α adrenergic receptors, and produces hypnosis in tadpoles. Azi-medetomidine competes with the α agonist clonidine at α adrenergic receptors, which is potentiated by photolabeling, and azi-medetomidine labels moieties on the α adrenergic receptor as determined by mass spectrometry in a manner consistent with a simulated model. This novel α adrenergic agonist photolabel can serve as a powerful tool for in vitro and in vivo investigations of adrenergic signaling.
Topics: Adrenergic alpha-2 Receptor Agonists; Amino Acid Sequence; Animals; Dose-Response Relationship, Drug; Humans; Ligands; Medetomidine; Photoaffinity Labels; Protein Structure, Secondary; Receptors, Adrenergic, alpha-2; Xenopus laevis
PubMed: 31638765
DOI: 10.1021/acschemneuro.9b00484 -
Physiological Reports Mar 2023Activation of thermogenic adipose tissue depots has been linked to improved metabolism and weight loss. To study the molecular regulation of adipocyte thermogenesis, we...
Activation of thermogenic adipose tissue depots has been linked to improved metabolism and weight loss. To study the molecular regulation of adipocyte thermogenesis, we performed RNA-Seq on brown adipose tissue (BAT), gonadal white adipose tissue (gWAT), and inguinal white adipose tissue (iWAT) from mice treated with β3-adrenoreceptor agonist CL316,243 (CL). Our analysis revealed diverse transcriptional profile and identified pathways in response to CL treatment. Differentially expressed genes (DEGs) in iWATCL were associated with the upregulation of pathways involved in cellular immune responses and with the upregulation of the browning program. We identified 39 DEGs in beige adipose which included certain heat shock proteins (Hspa1a and Hspa1b), and others suggesting potential associations with browning. Our results highlight transcriptional heterogeneity across adipose tissues and reveal genes specifically regulated in beige adipose, potentially aiding in identifying novel browning pathways.
Topics: Mice; Animals; Transcriptome; Adipose Tissue, White; Adipose Tissue; Adipose Tissue, Brown; Adipocytes; Adrenergic beta-3 Receptor Agonists; Obesity; Thermogenesis; Mice, Inbred C57BL
PubMed: 36967237
DOI: 10.14814/phy2.15646 -
CNS Drugs Jul 2020Potential relationships between β-adrenergic drugs and α-synuclein synthesis in Parkinson's disease (PD) have been recently suggested.
BACKGROUND
Potential relationships between β-adrenergic drugs and α-synuclein synthesis in Parkinson's disease (PD) have been recently suggested.
OBJECTIVE
This study investigated the putative association between β-adrenoceptor drug exposure and PD occurrence.
METHODS
A nested case-control study was performed in the Echantillon Généraliste des Bénéficiaires (EGB) (a 1/97th random sample of affiliates to the French Insurance System). Incident PD patients diagnosed between 01/01/2008 and 31/12/2017 (index date) were matched 1:1 to controls by gender, birth year, and insurance scheme. Exposure to any β-agonist and to any β-antagonist was compared between cases and controls within 1-2 years before the index date, and exposure to salbutamol and to propranolol was individualized. The association between PD and β-adrenoceptor drugs was investigated through conditional logistic regression models adjusted for potential confounding factors. Because of a statistical interaction between β-agonists and diabetes, results were stratified according to the presence of diabetes.
RESULTS
Among the 2225 incident PD patients identified in the EGB (mean age 75.6 ± 10.2 years, sex ratio 1.04), no significant association was found between PD and β-antagonists (adjusted odds ratio [aOR] 1.05 [95% confidence interval 0.91-1.20]), except for propranolol (aOR 2.11 [1.38-3.23]). For β-agonists, a protective association in non-diabetic patients (aOR 0.75 [0.60-0.93]) and an opposite and significant association in diabetic patients (aOR 1.61 [1.02-2.55]) were observed. Similar results were found with salbutamol.
CONCLUSION
This study did not identify an increased risk of PD occurrence after β-antagonist exposure, except for propranolol (potential protopathic bias). The discordant results observed with β-agonists in patients with or without diabetes deserve further exploration of the influence of diabetic comorbidity on PD occurrence and evolution.
Topics: Adrenergic Agonists; Adrenergic Antagonists; Aged; Aged, 80 and over; Case-Control Studies; Female; Humans; Male; Parkinson Disease; Receptors, Adrenergic; Risk Factors; Signal Transduction
PubMed: 32500347
DOI: 10.1007/s40263-020-00736-2 -
Trials Apr 2023Urgency-type urinary incontinence affects one in four older community-dwelling women and overlaps with other common aging-associated health syndromes such as cognitive...
TReating Incontinence for Underlying Mental and Physical Health (TRIUMPH): a study protocol for a multicenter, double-blinded, randomized, 3-arm trial to evaluate the multisystem effects of pharmacologic treatment strategies for urgency-predominant urinary incontinence in ambulatory older women.
BACKGROUND
Urgency-type urinary incontinence affects one in four older community-dwelling women and overlaps with other common aging-associated health syndromes such as cognitive impairment, physical mobility impairment, and depression. Observational studies have raised concern about potentially higher rates of delirium and dementia in older adults taking anticholinergic bladder medications, but few prospective data are available to evaluate the effects of these and other pharmacologic treatments for urgency incontinence on cognition and other multisystem functional domains important to older women.
METHODS
The TRIUMPH study is a randomized, double-blinded, 3-arm, parallel-group trial comparing the multisystem effects of anticholinergic versus beta-3-adrenergic agonist bladder therapy and versus no active bladder anti-spasmodic pharmacotherapy in older women with urgency incontinence. Women aged 60 years and older (target N = 270) who have chronic urgency-predominant urinary incontinence and either normal or mildly impaired cognition at baseline are recruited from the community by investigators based in northern California, USA. Participants are randomized in equal ratios to take identically encapsulated oral anticholinergic bladder therapy (in the form of tolterodine 2 mg extended release [ER]), oral beta-3 adrenergic agonist bladder therapy (mirabegron 25 mg ER), or placebo daily for 24 weeks, with the option of participant-directed dose titration (to tolterodine 4 mg ER, mirabegron 50 mg ER, or matching placebo daily). Participants also receive patient-oriented information and instructions about practicing first-line behavioral management strategies for incontinence. The primary outcome is change in composite cognitive function over 24 weeks assessed by a comprehensive battery of cognitive tests, with a secondary exploration of the persistence of change at 36 weeks. Secondary outcomes include changes over 24 and 36 weeks in domain-specific cognitive function; frequency, severity, and impact of urgency-associated urinary symptoms; physical function and balance; sleep quality and daytime sleepiness; psychological function; and bowel function.
DISCUSSION
The TRIUMPH trial addresses the need for rigorous evidence to guide counseling and decision-making for older women who are weighing the potential multisystem benefits and risks of pharmacologic treatments for urgency incontinence in order to preserve their day-to-day functioning, quality of life, and independence in older age.
TRIAL REGISTRATION
ClinicalTrials.gov NCT05362292. Registered on May 5, 2022.
Topics: Humans; Female; Middle Aged; Aged; Tolterodine Tartrate; Muscarinic Antagonists; Urinary Bladder, Overactive; Quality of Life; Prospective Studies; Urinary Incontinence; Cholinergic Antagonists; Adrenergic Agonists; Treatment Outcome; Double-Blind Method; Randomized Controlled Trials as Topic; Multicenter Studies as Topic
PubMed: 37085880
DOI: 10.1186/s13063-023-07279-z -
Drugs Jul 2023A growing number of clinical trials are documenting that adding a long-acting muscarinic antagonist (LAMA) to established asthma treatment with an inhaled corticosteroid...
A growing number of clinical trials are documenting that adding a long-acting muscarinic antagonist (LAMA) to established asthma treatment with an inhaled corticosteroid (ICS) and a long-acting β-agonist (LABA) is a treatment option that improves the health of patients with uncontrolled severe asthma even when therapy is optimized. These favorable results are the reason why the leading guidelines recommend triple therapy with ICS + LABA + LAMA in patients with asthma uncontrolled by medium- to high-dose ICS-LABA. However, we suggest adding LAMAs to ICS-LABAs at an earlier clinical stage. Such action could positively influence airflow limitation, exacerbations, and eosinophilic inflammation, conditions that are associated with acetylcholine (ACh) activity. It could also interrupt the vicious cycle related to a continuous release of ACh leading to the progressive expansion of neuronal plasticity resulting in small airway dysfunction. The utility of an earlier use of triple therapy in asthma should, in any case, be confirmed by statistically powered trials.
Topics: Humans; Muscarinic Antagonists; Adrenergic beta-2 Receptor Agonists; Administration, Inhalation; Asthma; Lung; Drug Therapy, Combination; Adrenal Cortex Hormones; Pulmonary Disease, Chronic Obstructive; Bronchodilator Agents
PubMed: 37303017
DOI: 10.1007/s40265-023-01897-2 -
Brain Research Apr 2020Emotionally significant stimuli, including potential threats from the external environment, trigger an increase in body temperature, a response known as emotional...
Emotionally significant stimuli, including potential threats from the external environment, trigger an increase in body temperature, a response known as emotional hyperthermia. Sympathetically-mediated brown adipose tissue (BAT) thermogenesis contributes substantially to this hyperthermic response. The systemic administration of α-adrenergic agonists is known to inhibit both febrile and shivering responses. In the present study, we investigated whether systemic administration of clonidine, a α-adrenoceptor agonist, attenuates the emotional hyperthermia evoked in conscious unrestrained rats suddenly confronted with a second (intruder) rat, itself confined to a small cage. Pre-implanted thermistors were used to measure BAT and body temperature in conscious, freely moving, male Sprague-Dawley rats. The rats were pre-treated with intraperitoneally administered vehicle (Ringer solution) or clonidine (1, 10 and 100 µg/kg). Clonidine, in a dose-dependent manner, reduced the intruder-elicited increases in BAT (log-dose linear regression F(1,16) = 9.52, R = 0.37, P < 0.01) and body temperature (F(1,16) = 6.48, R = 0.29, P < 0.05). We also investigated, in anesthetized rats, whether systemic clonidine administration inhibits BAT sympathetic nerve discharge evoked via activation of neurons in the lateral habenula (LHb) - a nucleus involved in the regulation of emotional hyperthermia. In anesthetized rats, clonidine abolished the BAT sympathetic nerve discharges elicited via bicuculline-mediated disinhibition of the LHb. These results suggest that activation of central α-adrenergic receptors attenuates the process of emotional hyperthermia by reduction of BAT thermogenesis.
Topics: Adipose Tissue, Brown; Adrenergic alpha-2 Receptor Agonists; Animals; Body Temperature; Clonidine; Emotions; Habenula; Hyperthermia; Male; Rats; Rats, Sprague-Dawley; Thermogenesis
PubMed: 31981679
DOI: 10.1016/j.brainres.2020.146678