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Molecular Metabolism Jan 2024Retinol saturase (RetSat) is an endoplasmic reticulum-localized oxidoreductase highly expressed in organs involved in lipid metabolism such as white (WAT) and brown...
OBJECTIVE
Retinol saturase (RetSat) is an endoplasmic reticulum-localized oxidoreductase highly expressed in organs involved in lipid metabolism such as white (WAT) and brown adipose tissue (BAT). Cold exposure was shown to increase RETSAT protein in BAT but its relevance for non-shivering thermogenesis, a process with beneficial effects on metabolic health, is unknown.
METHODS
We analyzed the regulation of RetSat expression in white and brown adipocytes and different murine adipose tissue depots upon β-adrenergic stimulation and cold exposure. RetSat function during the differentiation and β-adrenergic stimulation of brown adipocytes was dissected by loss-of-function experiments. Mice with BAT-specific deletion of RetSat were generated and exposed to cold. Gene expression in human WAT was analyzed and the effect of RetSat depletion on adipocyte lipolysis investigated.
RESULTS
We show that cold exposure induces RetSat expression in both WAT and BAT of mice via β-adrenergic signaling. In brown adipocytes, RetSat has minor effects on differentiation but is required for maximal thermogenic gene and protein expression upon β-adrenergic stimulation and mitochondrial respiration. In mice, BAT-specific deletion of RetSat impaired acute but not long-term adaptation to cold exposure. RetSat expression in subcutaneous WAT of humans correlates with the expression of genes related to mitochondrial function. Mechanistically, we found that RetSat depletion impaired β-agonist-induced lipolysis, a major regulator of thermogenic gene expression in adipocytes.
CONCLUSIONS
Thus, RetSat expression is under β-adrenergic control and determines thermogenic capacity of brown adipocytes and acute cold tolerance in mice. Modulating RetSat activity may allow for therapeutic interventions towards pathologies with inadequate metabolic activity.
Topics: Mice; Humans; Animals; Vitamin A; Lipolysis; Adrenergic Agents; Adipose Tissue, Brown; Adipocytes, Brown; Obesity
PubMed: 38128827
DOI: 10.1016/j.molmet.2023.101855 -
Vascular Health and Risk Management 2012β-blockers are effective antihypertensive agents and, together with diuretics, have been the cornerstone of pioneering studies showing their benefits on cardiovascular... (Review)
Review
β-blockers are effective antihypertensive agents and, together with diuretics, have been the cornerstone of pioneering studies showing their benefits on cardiovascular morbidity and mortality as a consequence of blood pressure reduction in patients with hypertension. However, evidence from recent meta-analyses have demonstrated no benefit afforded by atenolol compared with placebo in risk of mortality, myocardial infarction, or stroke, and a higher risk of mortality and stroke with atenolol/propranolol compared with other antihypertensive drug classes. Thus, the effect of these agents on cardiovascular morbidity and mortality in hypertensive patients, especially their use in uncomplicated hypertension, has remained largely controversial. However, it is recognized that the clinical studies used in these meta-analyses were mainly based on the older second-generation β-blockers, such as atenolol and metoprolol. Actually, considerable heterogeneity in, eg, pharmacokinetic, pharmacological, and physicochemical properties exists across the different classes of β-blockers, particularly between the second-generation and newer third-generation agents. Carvedilol is a vasodilating noncardioselective third-generation β-blocker, without the negative hemodynamic and metabolic effects of traditional β-blockers, which can be used as a cardioprotective agent. Compared with conventional β-blockers, carvedilol maintains cardiac output, has a reduced prolonged effect on heart rate, and reduces blood pressure by decreasing vascular resistance. Studies have also shown that carvedilol exhibits favorable effects on metabolic parameters, eg, glycemic control, insulin sensitivity, and lipid metabolism, suggesting that it could be considered in the treatment of patients with metabolic syndrome or diabetes. The present report provides an overview of the main clinical studies concerning carvedilol administered as either monotherapy or in combination with another antihypertensive or more frequently a diuretic agent, with particular focus on the additional benefits beyond blood pressure reduction.
Topics: Adrenergic beta-Antagonists; Animals; Antihypertensive Agents; Blood Pressure; Carbazoles; Carvedilol; Comorbidity; Drug Therapy, Combination; Evidence-Based Medicine; Humans; Hypertension; Patient Selection; Propanolamines; Risk Assessment; Treatment Outcome; Vasodilator Agents
PubMed: 22661898
DOI: 10.2147/VHRM.S31578 -
Report on Carcinogens : Carcinogen... 2011
Topics: Adrenergic Uptake Inhibitors; Animals; Antihypertensive Agents; Humans; Neoplasms; Reserpine
PubMed: 21863092
DOI: No ID Found -
The Primary Care Companion For CNS... Aug 2016To review currently available formulations and emphasize unmet needs in the pharmacologic management of attention-deficit/hyperactivity disorder (ADHD). (Review)
Review
OBJECTIVE
To review currently available formulations and emphasize unmet needs in the pharmacologic management of attention-deficit/hyperactivity disorder (ADHD).
DATA SOURCES
Publications and clinical trials were identified through PubMed and ClinicalTrials.gov, respectively. A Web-based search identified prescribing information for approved agents for treating ADHD, along with relevant guidelines and diagnostic criteria.
STUDY SELECTION
The following search terms were used: (1) ADHD or attention-deficit/hyperactivity disorder or ADD or attention deficit hyperactivity disorder and/or (2) amphetamine or methylphenidate or atomoxetine or guanfacine or clonidine. Additional searches were performed using product brand names, and clinical trial was applied as a filter. Relevant studies were only included if published in English-language peer-reviewed journals and if involved agents were currently available (or pursuing approval) in the United States. Reviews of literature prior to 2005 and from 2005 to 2008 have been published previously; therefore, the present search focused on studies published from January 2009 through May 2016. In addition, reference lists of review articles and relevant studies were also examined to help identify additional studies.
DATA EXTRACTION
A total of 578 publications were identified from the PubMed search, from which 426 publications were initially excluded based on review of the title and abstract. Reasons for exclusion included a focus on comorbid disorders, specific subpopulations, endpoints unrelated to improving ADHD symptomatology (eg, executive function, cognition, substance use), or quality of life measures. A more thorough assessment of the remaining citations, including publications and prescribing information, produced the final 219.
RESULTS
Pharmacotherapy with stimulant and nonstimulant options is the most common approach for treating ADHD in adults and children. Stimulants are mostly formulated as either tablets or capsules; however, the newer generation includes transdermal patches, oral suspensions (liquids), chewable tablets, and orally disintegrating tablets. Nonstimulants are available in oral capsule (atomoxetine) and tablet (guanfacine and clonidine) formulations.
CONCLUSIONS
Despite the broad range of treatment options currently available, nonadherence remains a significant problem in ADHD. While evidence is currently lacking, the availability of new formulations may improve adherence.
Topics: Adrenergic Agents; Amphetamines; Atomoxetine Hydrochloride; Attention Deficit Disorder with Hyperactivity; Central Nervous System Stimulants; Clinical Trials as Topic; Clonidine; Guanfacine; Humans; Methylphenidate; Treatment Outcome
PubMed: 27828696
DOI: 10.4088/PCC.16r01979 -
Indian Journal of Ophthalmology Jan 2011Congenital glaucoma is a global problem and poses a diagnostic and therapeutic challenge to the ophthalmologist. A detailed evaluation under general anesthesia is...
Congenital glaucoma is a global problem and poses a diagnostic and therapeutic challenge to the ophthalmologist. A detailed evaluation under general anesthesia is advisable to establish the diagnosis and plan for management. Medical therapy has a limited role and surgery remains the primary therapeutic modality. While goniotomy or trabeculotomy ab externo is valuable in the management of congenital glaucoma, primary combined trabeculotomy-trabeculectomy offers the best hope of success in advanced cases. Trabeculectomy with antifibrotic agent and glaucoma drainage devices has a role in the management of refractory cases, and cyclodestructive procedures should be reserved for patients where these procedures have failed. Early diagnosis, prompt therapeutic intervention and proper refractive correction are keys to success. Management of residual vision and visual rehabilitation should be an integral part of the management of children with low vision and lifelong follow-up is a must.
Topics: Adrenergic Agents; Adrenergic Antagonists; Carbonic Anhydrase Inhibitors; Cryotherapy; Glaucoma; Glaucoma Drainage Implants; Humans; Infant, Newborn; Light Coagulation; Mitomycin; Ophthalmologic Surgical Procedures; Prostaglandins; Trabeculectomy
PubMed: 21150027
DOI: 10.4103/0301-4738.73683 -
Nature Communications Mar 2024G protein-coupled receptors (GPCRs) constitute the largest family of membrane proteins and are important drug targets. The discovery of drugs targeting these receptors...
G protein-coupled receptors (GPCRs) constitute the largest family of membrane proteins and are important drug targets. The discovery of drugs targeting these receptors and their G protein signaling properties are based on assays mainly performed with modified receptors expressed in heterologous cells. However, GPCR responses may differ in their native environment. Here, by using highly sensitive G sensors, we reveal specific properties of G protein-mediated responses triggered by GABA, α adrenergic and cannabinoid CB1 receptors in primary neurons, different from those in heterologous cells. These include different profiles in the G protein subtypes-mediated responses, and differences in the potencies of some ligands even at similar receptor expression levels. Altogether, our results show the importance of using biosensors compatible with primary cells for evaluating the activities of endogenous GPCRs in their native environment.
Topics: Neurons; Receptors, G-Protein-Coupled; Signal Transduction; Adrenergic Agents; Biological Assay; GTP-Binding Protein alpha Subunits, Gi-Go
PubMed: 38443355
DOI: 10.1038/s41467-024-46177-z -
Behavioural Neurology 2006Pharmacotherapy may contribute to the rehabilitation of persons with posttraumatic cognitive impairments. This article reviews first the neurobiological consequences of... (Review)
Review
Pharmacotherapy may contribute to the rehabilitation of persons with posttraumatic cognitive impairments. This article reviews first the neurobiological consequences of traumatic brain injury with a particular emphasis on acute and long-term posttraumatic neurochemical disturbances. Studies of pharmacotherapies for posttraumatic cognitive impairments are reviewed next, and are organized according to medication class and the neurotransmitter system they affect most. Based on the evidence provided by that review, augmentation of posttraumatic cerebral catecholaminergic and cholinergic function are suggested as potentially useful neurochemical targets for pharmacologic intervention in this population. More specifically, it is suggested that persons with posttraumatic impairments in arousal, speed of processing, and possibly attention may benefit most from treatment with an agent that augments cerebral catecholaminergic function, and that persons whose predominant posttraumatic impairment is in the domain of memory may benefit most from treatment with cholinesterase inhibitors. Practical considerations regarding the use of pharmacotherapies for posttraumatic cognitive impairments are offered, and the need for additional research in this area is highlighted.
Topics: Adrenergic Agents; Biogenic Amines; Brain Injuries; Central Nervous System Stimulants; Cholinesterase Inhibitors; Cognition Disorders; Dopamine Agents; Glutamic Acid; Humans; Neurotransmitter Agents
PubMed: 16720958
DOI: 10.1155/2006/460592 -
Cell Reports May 2020Here, we show that β adrenergic signaling coordinately upregulates de novo lipogenesis (DNL) and thermogenesis in subcutaneous white adipose tissue (sWAT), and both...
Here, we show that β adrenergic signaling coordinately upregulates de novo lipogenesis (DNL) and thermogenesis in subcutaneous white adipose tissue (sWAT), and both effects are blocked in mice lacking the cAMP-generating G protein-coupled receptor Gs (Adipo-GsαKO) in adipocytes. However, UCP1 expression but not DNL activation requires rapamycin-sensitive mTORC1. Furthermore, β3-adrenergic agonist CL316243 readily upregulates thermogenic but not lipogenic genes in cultured adipocytes, indicating that additional regulators must operate on DNL in sWAT in vivo. We identify one such factor as thyroid hormone T3, which is elevated locally by adrenergic signaling. T3 administration to wild-type mice enhances both thermogenesis and DNL in sWAT. Mechanistically, T3 action on UCP1 expression in sWAT depends upon cAMP and is blocked in Adipo-GsαKO mice even as elevated DNL persists. Thus, T3 enhances sWAT thermogenesis by amplifying cAMP signaling, while its control of adipocyte DNL can be mediated independently of both cAMP and rapamycin-sensitive mTORC1.
Topics: Adipocytes; Adipose Tissue, Brown; Adipose Tissue, White; Adrenergic Agents; Animals; Lipogenesis; Mice, Transgenic; Signal Transduction; Thermogenesis; Thyroid Hormones
PubMed: 32375048
DOI: 10.1016/j.celrep.2020.107598 -
Dynamics of adrenergic signaling in cardiac myocytes and implications for pharmacological treatment.Journal of Theoretical Biology Jun 2021Dense innervation of the heart by the sympathetic nervous system (SNS) allows cardiac output to respond appropriately to the needs of the body under varying conditions,...
Dense innervation of the heart by the sympathetic nervous system (SNS) allows cardiac output to respond appropriately to the needs of the body under varying conditions, but occasionally the abrupt onset of SNS activity can trigger cardiac arrhythmias. Sympathetic activity leads to the release of norepinephrine (NE) onto cardiomyocytes, activating β-adrenergic receptors (β-ARs) and leading to the production of the second messenger cyclic AMP (cAMP). Upon sudden activation of β-ARs in experiments, intracellular cAMP can transiently rise to a high concentration before converging to a steady state level. Although changes to cellular cAMP concentration are important in modulating the overall cardiovascular response to sympathetic tone, the underlying mechanisms of the cAMP transients and the parameters that control their magnitude are unclear. We reduce a detailed computational model of the β-adrenergic signaling cascade to a system of two differential equations by eliminating extraneous variables and applying quasi-steady state approximation. The structure of the reduced model reveals that the large cAMP transients associated with abrupt β-AR activation are generated by the interplay of production/degradation of cAMP and desensitization/resensitization of β-ARs. The reduced model is used to predict how the dynamics of intracellular cAMP depend on the concentrations of norepinephrine (NE), phosphodiesterases 3 and 4 (PDE3,4), G-protein coupled receptor kinase 2 (GRK2), and β-AR, in healthy conditions and a simple model of early stages of heart failure. The key findings of the study are as follows: 1) Applying a reduced model of the dynamics of cardiac sympathetic signaling we show that the concentrations of two variables, cAMP and non-desensitized β-AR, capture the overall dynamics of sympathetic signaling; 2) The key factors influencing cAMP production are AC activity and PDE3,4 activity, while those that directly impact β-AR phosphorylation are GRK2 and PKA. Thus, disease states that affect sympathetic control of the heart can be thoroughly assessed by studying AC activity, PDE3,4, GRK2 and PKA activity, as these factors directly impact cAMP production/degradation and β-AR (de) phosphorylation and are therefore predicted to comprise the most effective pharmaceutical targets in diseases affecting cardiac β-adrenergic signaling.
Topics: Adrenergic Agents; Cyclic AMP; Humans; Myocytes, Cardiac; Receptors, Adrenergic, beta-1; Signal Transduction
PubMed: 33740423
DOI: 10.1016/j.jtbi.2021.110619 -
ESC Heart Failure Apr 2021Limited data are available regarding cardiac expression of molecules involved in heart failure (HF) pathophysiology. The majority of the studies have focused on...
Myocardial expression of somatotropic axis, adrenergic signalling, and calcium handling genes in heart failure with preserved ejection fraction and heart failure with reduced ejection fraction.
AIMS
Limited data are available regarding cardiac expression of molecules involved in heart failure (HF) pathophysiology. The majority of the studies have focused on end-stage HF with reduced ejection fraction (HFrEF) without comparison with healthy subjects, while no data are available with regard to HF with preserved ejection fraction (HFpEF). HFpEF is a condition whose multiple pathophysiological mechanisms are still not fully defined, with many proposed hypotheses remaining speculative due to limited access to human heart tissue. This study aimed at evaluating cardiac expression levels of key genes of interest in human biopsy samples from patients affected with HFrEF and HFpEF in order to possibly point out distinct phenotypes.
METHODS AND RESULTS
Total RNA was extracted from left ventricular cardiac biopsies collected from stable patients with HFrEF (n = 6) and HFpEF (n = 7) and healthy subjects (n = 9) undergoing elective cardiac surgery for valvular replacement, mitral valvuloplasty, aortic surgery, or coronary artery bypass. Real-time PCR was performed to evaluate the mRNA expression levels of genes involved in somatotropic axis regulation [IGF-1, IGF-1 receptor (IGF-1R), and GH receptor (GHR)], in adrenergic signalling (GRK2, GRK5, ADRB1, and ADRB2), in myocardial calcium handling (SERCA2), and in TNF-α. Patients with HFrEF and HFpEF showed reduced serum IGF-1 circulating levels when compared with controls (102 ± 35.6, 138 ± 11.5, and 160 ± 13.2 ng/mL, P < 0.001, respectively). At myocardial level, HFrEF showed significant decreased GHR and increased IGF-1R expressions when compared with HFpEF and controls (0.54 ± 0.27, 0.94 ± 0.25, and 0.84 ± 0.2, P < 0.05 and 1.52 ± 0.9, 1.06 ± 0.21, and 0.72 ± 0.12, P < 0.05, respectively), while no differences in the local expression of IGF-1 mRNA were detected among the groups (0.80 ± 0.45, 0.97 ± 0.18, and 0.63 ± 0.23, P = 0.09, respectively). With regard to calcium handling and adrenergic signalling, HFrEF displayed significant decreased levels of SERCA2 (0.19 ± 0.39, 0.82 ± 0.15, and 0.87 ± 0.32, P < 0.01) and increased levels of GRK2 (3.45 ± 2.94, 0.93 ± 0.12, and 0.80 ± 0.14, P < 0.01) and GRK5 (1.32 ± 0.70, 0.71 ± 0.14, and 0.77 ± 0.15, P < 0.05), while no significant difference was found in ADRB1 (0.66 ± 0.4, 0.83 ± 0.3, and 0.86 ± 0.4) and ADRB2 mRNA expression (0.65 ± 0.3, 0.66 ± 0.2, and 0.68 ± 0.1) when compared with HFpEF and controls. Finally, no changes in the local expression of TNF-α were detected among groups.
CONCLUSIONS
Heart failure with reduced ejection fraction and HFpEF patients with stable clinical condition display a distinct molecular milieu of genes involved in somatotropic axis regulation, calcium handling, and adrenergic derangement at a myocardial level. The unique opportunity to compare these results with a control group, as reference population, may contribute to better understand HF pathophysiology and to identify novel potential therapeutic targets that could be modulated to improve ventricular function in patients with HF.
Topics: Adrenergic Agents; Calcium; Heart Failure; Humans; Stroke Volume
PubMed: 33512777
DOI: 10.1002/ehf2.13067