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Carpéné C, Boulet N, Grolleau JL, Morin N. High doses of catecholamines activate glucose transport in human adipocytes independently from adrenoceptor stimulation or vanadium addition. World J Diabetes 2022; 13:37-53. [PMID: 35070058 PMCID: PMC8771263 DOI: 10.4239/wjd.v13.i1.37] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 04/26/2021] [Accepted: 12/28/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND When combined with vanadium salts, catecholamines strongly activate glucose uptake in rat and mouse adipocytes.
AIM To test whether catecholamines activate glucose transport in human adipocytes.
METHODS The uptake of 2-deoxyglucose (2-DG) was measured in adipocytes isolated from pieces of abdominal subcutaneous tissue removed from women undergoing reconstructive surgery. Pharmacological approaches with amine oxidase inhibitors, adrenoreceptor agonists and antioxidants were performed to unravel the mechanisms of action of noradrenaline or adrenaline (also named epinephrine).
RESULTS In human adipocytes, 45-min incubation with 100 µmol/L adrenaline or noradrenaline activated 2-DG uptake up to more than one-third of the maximal response to insulin. This stimulation was not reproduced with millimolar doses of dopamine or serotonin and was not enhanced by addition of vanadate to the incubation medium. Among various natural amines and adrenergic agonists tested, no other molecule was more efficient than adrenaline and noradrenaline in stimulating 2-DG uptake. The effect of the catecholamines was not impaired by pargyline and semicarbazide, contrarily to that of benzylamine or methylamine, which are recognized substrates of semicarbazide-sensitive amine oxidase. Hydrogen peroxide at 1 mmol/L activated hexose uptake but not pyrocatechol or benzoquinone, and only the former was potentiated by vanadate. Catalase and the phosphoinositide 3-kinase inhibitor wortmannin inhibited adrenaline-induced activation of 2-DG uptake.
CONCLUSION High doses of catecholamines exert insulin-like actions on glucose transport in human adipocytes. At submillimolar doses, vanadium did not enhance this catecholamine activation of glucose transport. Consequently, this dismantles our previous suggestion to combine the metal ion with catecholamines to improve the benefit/risk ratio of vanadium-based antidiabetic approaches.
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Affiliation(s)
- Christian Carpéné
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM UMR1297, Toulouse 31432, France
| | - Nathalie Boulet
- Team Dinamix, Institute of Metabolic and Cardiovascular Diseases (I2MC), Paul Sabatier University, Toulouse 31432, France
| | | | - Nathalie Morin
- Faculté de Pharmacie de Paris, Université de Paris, INSERM UMR-S 1139, 3PHM, Paris 75006, France
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2
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Beneficial effects of metformin supplementation in hypothalamic paraventricular nucleus and arcuate nucleus of type 2 diabetic rats. Toxicol Appl Pharmacol 2022; 437:115893. [PMID: 35085591 DOI: 10.1016/j.taap.2022.115893] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 01/11/2022] [Accepted: 01/19/2022] [Indexed: 12/13/2022]
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Nigro SC, Nolan R, Boemio N. Probable Tamsulosin-Induced Hyperglycemia: A Case Study. Clin Diabetes 2022; 40:113-115. [PMID: 35221482 PMCID: PMC8865795 DOI: 10.2337/cd21-0018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Affiliation(s)
- Stefanie C. Nigro
- Department of Pharmacy Practice, UConn School of Pharmacy, Storrs, CT
- Corresponding author: Stefanie C. Nigro,
| | - Ryan Nolan
- PharmD candidate, UConn School of Pharmacy, Storrs, CT
| | - Nicholas Boemio
- Optum Care Network of Connecticut/ProHealth Physicians, Farmington, CT
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4
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Perez DM. Targeting Adrenergic Receptors in Metabolic Therapies for Heart Failure. Int J Mol Sci 2021; 22:5783. [PMID: 34071350 PMCID: PMC8198887 DOI: 10.3390/ijms22115783] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 05/20/2021] [Accepted: 05/22/2021] [Indexed: 12/14/2022] Open
Abstract
The heart has a reduced capacity to generate sufficient energy when failing, resulting in an energy-starved condition with diminished functions. Studies have identified numerous changes in metabolic pathways in the failing heart that result in reduced oxidation of both glucose and fatty acid substrates, defects in mitochondrial functions and oxidative phosphorylation, and inefficient substrate utilization for the ATP that is produced. Recent early-phase clinical studies indicate that inhibitors of fatty acid oxidation and antioxidants that target the mitochondria may improve heart function during failure by increasing compensatory glucose oxidation. Adrenergic receptors (α1 and β) are a key sympathetic nervous system regulator that controls cardiac function. β-AR blockers are an established treatment for heart failure and α1A-AR agonists have potential therapeutic benefit. Besides regulating inotropy and chronotropy, α1- and β-adrenergic receptors also regulate metabolic functions in the heart that underlie many cardiac benefits. This review will highlight recent studies that describe how adrenergic receptor-mediated metabolic pathways may be able to restore cardiac energetics to non-failing levels that may offer promising therapeutic strategies.
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Affiliation(s)
- Dianne M Perez
- The Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195, USA
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5
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Perez DM. Current Developments on the Role of α 1-Adrenergic Receptors in Cognition, Cardioprotection, and Metabolism. Front Cell Dev Biol 2021; 9:652152. [PMID: 34113612 PMCID: PMC8185284 DOI: 10.3389/fcell.2021.652152] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 04/29/2021] [Indexed: 12/13/2022] Open
Abstract
The α1-adrenergic receptors (ARs) are G-protein coupled receptors that bind the endogenous catecholamines, norepinephrine, and epinephrine. They play a key role in the regulation of the sympathetic nervous system along with β and α2-AR family members. While all of the adrenergic receptors bind with similar affinity to the catecholamines, they can regulate different physiologies and pathophysiologies in the body because they couple to different G-proteins and signal transduction pathways, commonly in opposition to one another. While α1-AR subtypes (α1A, α1B, α1C) have long been known to be primary regulators of vascular smooth muscle contraction, blood pressure, and cardiac hypertrophy, their role in neurotransmission, improving cognition, protecting the heart during ischemia and failure, and regulating whole body and organ metabolism are not well known and are more recent developments. These advancements have been made possible through the development of transgenic and knockout mouse models and more selective ligands to advance their research. Here, we will review the recent literature to provide new insights into these physiological functions and possible use as a therapeutic target.
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Affiliation(s)
- Dianne M Perez
- The Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH, United States
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6
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Fontaine J, Tavernier G, Morin N, Carpéné C. Vanadium-dependent activation of glucose transport in adipocytes by catecholamines is not mediated via adrenoceptor stimulation or monoamine oxidase activity. World J Diabetes 2020; 11:622-643. [PMID: 33384769 PMCID: PMC7754167 DOI: 10.4239/wjd.v11.i12.622] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 10/12/2020] [Accepted: 10/26/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Benzylamine and methylamine activate glucose uptake in adipocytes. For tyramine, this effect has even been extended to cardiomyocytes. AIM To investigate the effects of catecholamines and other amines on glucose uptake. METHODS A screening compared 25 biogenic amines on 2-deoxyglucose (2-DG) uptake activation in rat adipocytes. Pharmacological approaches and transgenic mouse models were then used to decipher the mode of action of several hits. RESULTS In rat adipocytes, insulin stimulation of 2-DG uptake was reproduced with catecholamines. 100 µmol/L or 1 mmol/L adrenaline, noradrenaline, dopamine and deoxyepinephrine, maximally activated hexose transport only when sodium orthovanadate was added at 100 µmol/L. Such activation was similar to that already reported for benzylamine, methylamine and tyramine, well-recognized substrates of semicarbazide-sensitive amine oxidase (SSAO) and monoamine oxidase (MAO). Several, but not all, tested agonists of β-adrenoreceptors (β-ARs) also activated glucose transport while α-AR agonists were inactive. Lack of blockade by α- and β-AR antagonists indicated that catecholamine-induced 2-DG uptake was not mediated by AR stimulation. Adipocytes from mice lacking β1-, β2- and β3-ARs (triple KO) also responded to millimolar doses of adrenaline or noradrenaline by activating hexose transport in the presence of 100 µmol/L vanadate. The MAO blocker pargyline, and SSAO inhibitors did not block the effects of adrenaline or noradrenaline plus vanadate, which were blunted by antioxidants. CONCLUSION Catecholamines exert unexpected insulin-like actions in adipocytes when combined with vanadium. For limiting insulin resistance by activating glucose consumption at least in fat stores, we propose that catecholamine derivatives combined with vanadium can generate novel complexes that may have low toxicity and promising anti-diabetic properties.
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Affiliation(s)
- Jessica Fontaine
- Institut des Maladies Métaboliques et Cardiovasculaires, Institut National de la Santé et de la Recherche Médicale, INSERM UMR1048, Université Paul Sabatier Toulouse III, Toulouse 31432, France
| | - Geneviève Tavernier
- Institut des Maladies Métaboliques et Cardiovasculaires, Institut National de la Santé et de la Recherche Médicale, INSERM UMR1048, Université Paul Sabatier Toulouse III, Toulouse 31432, France
| | - Nathalie Morin
- Institut des Maladies Métaboliques et Cardiovasculaires, Institut National de la Santé et de la Recherche Médicale, INSERM UMR1048, Université Paul Sabatier Toulouse III, Toulouse 31432, France
- INSERM UMR 1139 Faculté de Pharmacie, Université de Paris, Paris 75006, France
| | - Christian Carpéné
- Institut des Maladies Métaboliques et Cardiovasculaires, Institut National de la Santé et de la Recherche Médicale, INSERM UMR1048, Université Paul Sabatier Toulouse III, Toulouse 31432, France
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7
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Chowdhury HH. Differences in cytosolic glucose dynamics in astrocytes and adipocytes measured by FRET-based nanosensors. Biophys Chem 2020; 261:106377. [PMID: 32302866 DOI: 10.1016/j.bpc.2020.106377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Revised: 04/08/2020] [Accepted: 04/08/2020] [Indexed: 11/17/2022]
Abstract
The cellular response to fluctuations in blood glucose levels consists of integrative regulation of cell glucose uptake and glucose utilization in the cytosol, resulting in altered levels of glucose in the cytosol. Cytosolic glucose is difficult to be measured in the intact tissue, however recently methods have become available that allow measurements of glucose in single living cells with fluorescence resonance energy transfer (FRET) based protein sensors. By studying the dynamics of cytosolic glucose levels in different experimental settings, we can gain insights into the properties of plasma membrane permeability to glucose and glucose utilization in the cytosol, and how these processes are modulated by different environmental conditions, agents and enzymes. In this review, we compare the cytosolic regulation of glucose in adipocytes and astrocytes - two important regulators of energy balance and glucose homeostasis in whole body and brain, respectively, with particular emphasis on the data obtained with FRET based protein sensors as well as other biochemical and molecular approaches.
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Affiliation(s)
- Helena H Chowdhury
- Laboratory of Neuroendocrinology - Molecular Cell Physiology, Institute of Pathophysiology, University of Ljubljana, Faculty of Medicine, 1000 Ljubljana, Slovenia; Laboratory of Cell Engineering, Celica Biomedical, 1000 Ljubljana, Slovenia.
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8
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Riddy DM, Delerive P, Summers RJ, Sexton PM, Langmead CJ. G Protein-Coupled Receptors Targeting Insulin Resistance, Obesity, and Type 2 Diabetes Mellitus. Pharmacol Rev 2018; 70:39-67. [PMID: 29233848 DOI: 10.1124/pr.117.014373] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Accepted: 09/13/2017] [Indexed: 03/21/2025] Open
Abstract
G protein-coupled receptors (GPCRs) continue to be important discovery targets for the treatment of type 2 diabetes mellitus (T2DM). Many GPCRs are directly involved in the development of insulin resistance and β-cell dysfunction, and in the etiology of inflammation that can lead to obesity-induced T2DM. This review summarizes the current literature describing a number of well-validated GPCR targets, but also outlines several new and promising targets for drug discovery. We highlight the importance of understanding the role of these receptors in the disease pathology, and their basic pharmacology, which will pave the way to the development of novel pharmacological probes that will enable these targets to fulfill their promise for the treatment of these metabolic disorders.
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Affiliation(s)
- Darren M Riddy
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., R.J.S., P.M.S., C.J.L.); and Institut de Recherches Servier, Pôle d'Innovation Thérapeutique Métabolisme, Suresnes, France (P.D.)
| | - Philippe Delerive
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., R.J.S., P.M.S., C.J.L.); and Institut de Recherches Servier, Pôle d'Innovation Thérapeutique Métabolisme, Suresnes, France (P.D.)
| | - Roger J Summers
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., R.J.S., P.M.S., C.J.L.); and Institut de Recherches Servier, Pôle d'Innovation Thérapeutique Métabolisme, Suresnes, France (P.D.)
| | - Patrick M Sexton
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., R.J.S., P.M.S., C.J.L.); and Institut de Recherches Servier, Pôle d'Innovation Thérapeutique Métabolisme, Suresnes, France (P.D.)
| | - Christopher J Langmead
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., R.J.S., P.M.S., C.J.L.); and Institut de Recherches Servier, Pôle d'Innovation Thérapeutique Métabolisme, Suresnes, France (P.D.)
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9
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Seeling T, Čikoš Š, Grybel KJ, Janštová Ž, Pendzialek SM, Schindler M, Špirková A, Santos AN. A Diabetic Pregnancy Alters the Expression of Stress-Related Receptors in Gastrulating Rabbit Blastocyst and in the Reproductive Tract. Reprod Sci 2017; 25:174-184. [DOI: 10.1177/1933719117707055] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Tom Seeling
- Department of Anatomy and Cell Biology, Faculty of Medicine, Martin Luther University Halle-Wittenberg, Halle/Saale, Germany
| | - Štefan Čikoš
- Institute of Animal Physiology, Slovak Academy of Science, Kosice, Slovakia
| | - Katarzyna J. Grybel
- Department of Anatomy and Cell Biology, Faculty of Medicine, Martin Luther University Halle-Wittenberg, Halle/Saale, Germany
| | - Žofia Janštová
- Institute of Animal Physiology, Slovak Academy of Science, Kosice, Slovakia
| | - S. Mareike Pendzialek
- Department of Anatomy and Cell Biology, Faculty of Medicine, Martin Luther University Halle-Wittenberg, Halle/Saale, Germany
| | - Maria Schindler
- Department of Anatomy and Cell Biology, Faculty of Medicine, Martin Luther University Halle-Wittenberg, Halle/Saale, Germany
| | - Alexandra Špirková
- Institute of Animal Physiology, Slovak Academy of Science, Kosice, Slovakia
| | - Anne Navarrete Santos
- Department of Anatomy and Cell Biology, Faculty of Medicine, Martin Luther University Halle-Wittenberg, Halle/Saale, Germany
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10
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Shi T, Papay RS, Perez DM. The role of α 1-adrenergic receptors in regulating metabolism: increased glucose tolerance, leptin secretion and lipid oxidation. J Recept Signal Transduct Res 2016; 37:124-132. [PMID: 27277698 DOI: 10.1080/10799893.2016.1193522] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The role of α1-adrenergic receptors (α1-ARs) and their subtypes in metabolism is not well known. Most previous studies were performed before the advent of transgenic mouse models and utilized transformed cell lines and poorly selective antagonists. We have now studied the metabolic regulation of the α1A- and α1B-AR subtypes in vivo using knock-out (KO) and transgenic mice that express a constitutively active mutant (CAM) form of the receptor, assessing subtype-selective functions. CAM mice increased glucose tolerance while KO mice display impaired glucose tolerance. CAM mice increased while KO decreased glucose uptake into white fat tissue and skeletal muscle with the CAM α1A-AR showing selective glucose uptake into the heart. Using indirect calorimetry, both CAM mice demonstrated increased whole body fatty acid oxidation, while KO mice preferentially oxidized carbohydrate. CAM α1A-AR mice displayed significantly decreased fasting plasma triglycerides and glucose levels while α1A-AR KO displayed increased levels of triglycerides and glucose. Both CAM mice displayed increased plasma levels of leptin while KO mice decreased leptin levels. Most metabolic effects were more efficacious with the α1A-AR subtype. Our results suggest that stimulation of α1-ARs results in a favorable metabolic profile of increased glucose tolerance, cardiac glucose uptake, leptin secretion and increased whole body lipid metabolism that may contribute to its previously recognized cardioprotective and neuroprotective benefits.
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Affiliation(s)
- Ting Shi
- a Department of Molecular Cardiology , Lerner Research Institute, Cleveland Clinic Foundation , Cleveland , OH , USA
| | - Robert S Papay
- a Department of Molecular Cardiology , Lerner Research Institute, Cleveland Clinic Foundation , Cleveland , OH , USA
| | - Dianne M Perez
- a Department of Molecular Cardiology , Lerner Research Institute, Cleveland Clinic Foundation , Cleveland , OH , USA
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11
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Bulloch JM, Daly CJ. Autonomic nerves and perivascular fat: interactive mechanisms. Pharmacol Ther 2014; 143:61-73. [PMID: 24560685 DOI: 10.1016/j.pharmthera.2014.02.005] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2014] [Accepted: 02/03/2014] [Indexed: 12/31/2022]
Abstract
The evidence describing the autonomic innervation of body fat is reviewed with a particular focus on the role of the sympathetic neurotransmitters. In compiling the evidence, a strong case emerges for the interaction between autonomic nerves and perivascular adipose tissue (PVAT). Adipocytes have been shown to express receptors for neurotransmitters released from nearby sympathetic varicosities such as adrenoceptors (ARs), purinoceptors and receptors for neuropeptide Y (NPY). Noradrenaline can modulate both lipolysis (via α2- and β3-ARs) and lipogenesis (via α1- and β3-ARs). ATP can inhibit lipolysis (via P1 purinoceptors) or stimulate lipolysis (via P2y purinoceptors). NPY, which can be produced by adipocytes and sympathetic nerves, inhibits lipolysis. Thus the sympathetic triad of transmitters can influence adipocyte free fatty acid (FFA) content. Substance P (SP) released from sensory nerves has also been shown to promote lipolysis. Therefore, we propose a mechanism whereby sympathetic neurotransmission can simultaneously activate smooth muscle cells in the tunica media to cause vasoconstriction and alter FFA content and release from adjacent adipocytes in PVAT. The released FFA can influence endothelial function. Adipocytes also release a range of vasoactive substances, both relaxing and contractile factors, including adiponectin and reactive oxygen species. The action of adipokines (such as adiponectin) and reactive oxygen species (ROS) on cells of the vascular adventitia and nerves has yet to be fully elucidated. We hypothesise a strong link between PVAT and autonomic fibres and suggest that this poorly understood relationship is extremely important for normal vascular function and warrants a detailed study.
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Affiliation(s)
- Janette M Bulloch
- School of Science, University of the West of Scotland, Hamilton ML3 0JB, Scotland.
| | - Craig J Daly
- School of Life Sciences, University of Glasgow, Glasgow G128QQ, Scotland.
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12
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Boyda HN, Procyshyn RM, Pang CCY, Barr AM. Peripheral adrenoceptors: the impetus behind glucose dysregulation and insulin resistance. J Neuroendocrinol 2013; 25:217-28. [PMID: 23140239 DOI: 10.1111/jne.12002] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2012] [Revised: 10/10/2012] [Accepted: 11/04/2012] [Indexed: 12/20/2022]
Abstract
It is now accepted that several pharmacological drug treatments trigger clinical manifestations of glucose dysregulation, such as hyperglycaemia, glucose intolerance and insulin resistance, in part through poorly understood mechanisms. Persistent sympathoadrenal activation is linked to glucose dysregulation and insulin resistance, both of which significantly increase the risk of emergent endocrinological disorders, including metabolic syndrome and type 2 diabetes mellitus. Through the use of targeted mutagenesis and pharmacological methods, preclinical and clinical research has confirmed physiological glucoregulatory roles for several peripheral α- and β-adrenoceptor subtypes. Adrenoceptor isoforms in the pancreas (α(2A) and β(2) ), skeletal muscle (α(1A) and β(2) ), liver (α(1A & B) and β(2) ) and adipose tissue (α(1A) and β(1 & 3) ) are convincing aetiological targets that account for both immediate and long-lasting alterations in blood glucose homeostasis. Because significant overlap exists between the therapeutic applications of numerous classes of drugs and their associated adverse side-effects, a better understanding of peripheral adrenoceptor-mediated glucose metabolism is thus warranted. Therefore, at the same time as providing a brief review of glucose homeostasis in the periphery, the present review addresses both functional and pathophysiological roles of the mammalian α(1) , α(2) , and β-adrenoceptor isoforms in whole-body glucose turnover. We highlight evidence relating to the clinical use of common adrenergic drugs and their impacts on glucose metabolism.
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Affiliation(s)
- H N Boyda
- Department of Anesthesiology, Pharmacology & Therapeutics, University of British Columbia, Vancouver, Canada.
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Liu J, Bisschop PH, Eggels L, Foppen E, Ackermans MT, Zhou JN, Fliers E, Kalsbeek A. Intrahypothalamic estradiol regulates glucose metabolism via the sympathetic nervous system in female rats. Diabetes 2013; 62:435-43. [PMID: 23139356 PMCID: PMC3554366 DOI: 10.2337/db12-0488] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Long-term reduced hypothalamic estrogen signaling leads to increased food intake and decreased locomotor activity and energy expenditure, and ultimately results in obesity and insulin resistance. In the current study, we aimed to determine the acute obesity-independent effects of hypothalamic estrogen signaling on glucose metabolism. We studied endogenous glucose production (EGP) and insulin sensitivity during selective modulation of systemic or intrahypothalamic estradiol (E2) signaling in rats 1 week after ovariectomy (OVX). OVX caused a 17% decrease in plasma glucose, which was completely restored by systemic E2. Likewise, the administration of E2 by microdialysis, either in the hypothalamic paraventricular nucleus (PVN) or in the ventromedial nucleus (VMH), restored plasma glucose. The infusion of an E2 antagonist via reverse microdialysis into the PVN or VMH attenuated the effect of systemic E2 on plasma glucose. Furthermore, E2 administration in the VMH, but not in the PVN, increased EGP and induced hepatic insulin resistance. E2 administration in both the PVN and the VMH resulted in peripheral insulin resistance. Finally, sympathetic, but not parasympathetic, hepatic denervation blunted the effect of E2 in the VMH on both EGP and hepatic insulin sensitivity. In conclusion, intrahypothalamic estrogen regulates peripheral and hepatic insulin sensitivity via sympathetic signaling to the liver.
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Affiliation(s)
- Ji Liu
- Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Meibergdreef Amsterdam, the Netherlands
- Key Laboratory of Brain Function and Diseases, School of Life Sciences, University of Science and Technology of China, Chinese Academy of Sciences, Hefei, Anhui, People's Republic of China
- Department of Hypothalamic Integration Mechanisms, Netherlands Institute of Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Meibergdreef, Amsterdam, the Netherlands
| | - Peter H. Bisschop
- Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Meibergdreef Amsterdam, the Netherlands
| | - Leslie Eggels
- Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Meibergdreef Amsterdam, the Netherlands
| | - Ewout Foppen
- Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Meibergdreef Amsterdam, the Netherlands
- Department of Hypothalamic Integration Mechanisms, Netherlands Institute of Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Meibergdreef, Amsterdam, the Netherlands
| | - Mariette T. Ackermans
- Department of Clinical Chemistry, Laboratory of Endocrinology, Academic Medical Center, University of Amsterdam, Meibergdreef, Amsterdam, the Netherlands
| | - Jiang-Ning Zhou
- Key Laboratory of Brain Function and Diseases, School of Life Sciences, University of Science and Technology of China, Chinese Academy of Sciences, Hefei, Anhui, People's Republic of China
- Corresponding author: Jiang-Ning Zhou,
| | - Eric Fliers
- Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Meibergdreef Amsterdam, the Netherlands
| | - Andries Kalsbeek
- Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Meibergdreef Amsterdam, the Netherlands
- Department of Hypothalamic Integration Mechanisms, Netherlands Institute of Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Meibergdreef, Amsterdam, the Netherlands
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14
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Tobin L, Simonsen L, Galbo H, Bülow J. Vascular and metabolic effects of adrenaline in adipose tissue in type 2 diabetes. Nutr Diabetes 2012; 2:e46. [PMID: 23446661 PMCID: PMC3461355 DOI: 10.1038/nutd.2012.19] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Objective: The aim was to investigate adipose tissue vascular and metabolic effects of an adrenaline infusion in vivo in subjects with and without type 2 diabetes mellitus (T2DM). Design: Clinical intervention study with 1-h intravenous adrenaline infusion. Subjects: Eight male overweight T2DM subjects and eight male weight-matched, non-T2DM subjects were studied before, during and after an 1-h intravenous adrenaline infusion. Adipose tissue blood flow (ATBF) was determined by 133Xenon wash-out technique, and microvascular volume in the adipose tissue was studied by contrast-enhanced ultrasound imaging. Adipose tissue fluxes of glycerol, non-esterified fatty acids (NEFA), triacylglycerol and glucose were measured by Fick's principle after catherisation of a radial artery and a vein draining the abdominal, subcutaneous adipose tissue. Results: ATBF increased similarly in both groups during the adrenaline infusion. One hour post adrenaline, ATBF was still increased in overweight T2DM subjects. Adrenaline increased microvascular volume in non-T2DM subjects while this response was impaired in overweight T2DM subjects. Adrenaline-induced increase in lipolysis was similar in both groups, but NEFA output from adipose tissue was delayed in overweight T2DM subjects. Glucose uptake in adipose tissue increased in non-T2DM subjects during adrenaline infusion but was unchanged in overweight T2DM subjects. This results in a delayed excess release of NEFA from the adipose tissue in overweight T2DM subjects after cessation of the adrenaline infusion. Conclusion: Capillaries in the adipose tissue are recruited by adrenaline in non-T2DM subjects; however, this response is impaired in overweight T2DM subjects. NEFA, released in adipose tissue during adrenaline stimulation, is insufficiently re-esterified in situ in overweight T2DM subjects, probably owing to increased ATBF after adrenaline infusion and inability to increase adipose tissue glucose uptake.
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Affiliation(s)
- L Tobin
- Department of Clinical Physiology and Nuclearmedicine, Bispebjerg Hospital, University of Copenhagen, Copenhagen NV, Denmark
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15
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Liu F, He K, Yang X, Xu N, Liang Z, Xu M, Zhao X, Han Q, Zhang Y. α1A-adrenergic receptor induces activation of extracellular signal-regulated kinase 1/2 through endocytic pathway. PLoS One 2011; 6:e21520. [PMID: 21738688 PMCID: PMC3125289 DOI: 10.1371/journal.pone.0021520] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2011] [Accepted: 05/30/2011] [Indexed: 11/22/2022] Open
Abstract
G protein-coupled receptors (GPCRs) activate mitogen-activated protein kinases through a number of distinct pathways in cells. Increasing evidence has suggested that endosomal signaling has an important role in receptor signal transduction. Here we investigated the involvement of endocytosis in α1A-adrenergic receptor (α1A-AR)-induced activation of extracellular signal-regulated kinase 1/2 (ERK1/2). Agonist-mediated endocytic traffic of α1A-AR was assessed by real-time imaging of living, stably transfected human embryonic kidney 293A cells (HEK-293A). α1A-AR was internalized dynamically in cells with agonist stimulation, and actin filaments regulated the initial trafficking of α1A-AR. α1A-AR-induced activation of ERK1/2 but not p38 MAPK was sensitive to disruption of endocytosis, as demonstrated by 4°C chilling, dynamin mutation and treatment with cytochalasin D (actin depolymerizing agent). Activation of protein kinase C (PKC) and C-Raf by α1A-AR was not affected by 4°C chilling or cytochalasin D treatment. U73122 (a phospholipase C [PLC] inhibitor) and Ro 31–8220 (a PKC inhibitor) inhibited α1B-AR- but not α1A-AR-induced ERK1/2 activation. These data suggest that the endocytic pathway is involved in α1A-AR-induced ERK1/2 activation, which is independent of Gq/PLC/PKC signaling.
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Affiliation(s)
- Fei Liu
- Institute of Vascular Medicine, Peking University Third Hospital, and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, China
| | - Kangmin He
- Institute of Vascular Medicine, Peking University Third Hospital, and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, China
| | - Xinxing Yang
- Beijing National Laboratory for Molecular Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Biodynamic Optical Imaging Center, Peking University, Beijing, China
| | - Ning Xu
- Institute of Vascular Medicine, Peking University Third Hospital, and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, China
| | - Zhangyi Liang
- Beijing National Laboratory for Molecular Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Biodynamic Optical Imaging Center, Peking University, Beijing, China
| | - Ming Xu
- Institute of Vascular Medicine, Peking University Third Hospital, and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, China
| | - Xinsheng Zhao
- Beijing National Laboratory for Molecular Sciences, State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Biodynamic Optical Imaging Center, Peking University, Beijing, China
| | - Qide Han
- Institute of Vascular Medicine, Peking University Third Hospital, and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, China
| | - Youyi Zhang
- Institute of Vascular Medicine, Peking University Third Hospital, and Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, Beijing, China
- * E-mail:
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16
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Pharmacological modulation of dopamine receptor D2-mediated transmission alters the metabolic phenotype of diet induced obese and diet resistant C57Bl6 mice. EXPERIMENTAL DIABETES RESEARCH 2011; 2011:928523. [PMID: 21603181 PMCID: PMC3096057 DOI: 10.1155/2011/928523] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/09/2010] [Accepted: 02/09/2011] [Indexed: 11/18/2022]
Abstract
High fat feeding induces a variety of obese and lean phenotypes in inbred rodents. Compared to Diet Resistant (DR) rodents, Diet Induced Obese (DIO) rodents are insulin resistant and have a reduced dopamine receptor D2 (DRD2) mediated tone. We hypothesized that this differing dopaminergic tone contributes to the distinct metabolic profiles of these animals.
C57Bl6 mice were classified as DIO or DR based on their weight gain during 10 weeks of high fat feeding. Subsequently DIO mice were treated with the DRD2 agonist bromocriptine and DR mice with the DRD2 antagonist haloperidol for 2 weeks.
Compared to DR mice, the bodyweight of DIO mice was higher and their insulin sensitivity decreased. Haloperidol treatment reduced the voluntary activity and energy expenditure of DR mice and induced insulin resistance in these mice. Conversely, bromocriptine treatment tended to reduce bodyweight and voluntary activity, and reinforce insulin action in DIO mice.
These results show that DRD2 activation partly redirects high fat diet induced metabolic anomalies in obesity-prone mice. Conversely, blocking DRD2 induces an adverse metabolic profile in mice that are inherently resistant to the deleterious effects of high fat food. This suggests that dopaminergic neurotransmission is involved in the control of metabolic phenotype.
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17
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Docherty JR. Subtypes of functional alpha1-adrenoceptor. Cell Mol Life Sci 2010; 67:405-17. [PMID: 19862476 PMCID: PMC11115521 DOI: 10.1007/s00018-009-0174-4] [Citation(s) in RCA: 139] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2009] [Revised: 09/11/2009] [Accepted: 10/05/2009] [Indexed: 11/29/2022]
Abstract
In this review, subtypes of functional alpha1-adrenoceptor are discussed. These are cell membrane receptors, belonging to the seven-transmembrane-spanning G-protein-linked family of receptors, which respond to the physiological agonist noradrenaline. alpha1-Adrenoceptors can be divided into alpha1A-, alpha1B- and alpha1D-adrenoceptors, all of which mediate contractile responses involving Gq/11 and inositol phosphate turnover. A fourth alpha1-adrenoceptor, the alpha1L-, represents a functional phenotype of the alpha1A-adrenoceptor. alpha1-Adrenoceptor subtype knock-out mice have refined our knowledge of the functions of alpha-adrenoceptor subtypes, particuarly as subtype-selective agonists and antagonists are not available for all subtypes. alpha1-Adrenoceptors function as stimulatory receptors involved particularly in smooth muscle contraction, especially contraction of vascular smooth muscle, both in local vasoconstriction and in the control of blood pressure and temperature, and contraction of the prostate and bladder neck. Central actions are now being elucidated.
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MESH Headings
- Animals
- Blood Pressure/physiology
- Body Temperature Regulation
- Drug Inverse Agonism
- GTP-Binding Protein alpha Subunits, Gq-G11/metabolism
- Inositol Phosphates/metabolism
- Mice
- Mice, Knockout
- Muscle, Smooth/physiology
- Muscle, Smooth, Vascular/physiology
- Receptors, Adrenergic, alpha-1/classification
- Receptors, Adrenergic, alpha-1/metabolism
- Receptors, Adrenergic, alpha-1/physiology
- Second Messenger Systems/physiology
- Vasoconstriction/physiology
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Affiliation(s)
- James R Docherty
- Department of Physiology, Royal College of Surgeons in Ireland, 123, St. Stephen's Green, Dublin 2, Ireland.
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18
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Widegren U, Hickner RC, Jorfeldt L, Henriksson J. Muscle blood flow response to mental stress and adrenaline infusion in man: microdialysis ethanol technique compared to (133)Xe clearance and venous occlusion plethysmography. Clin Physiol Funct Imaging 2010; 30:152-61. [PMID: 20113316 DOI: 10.1111/j.1475-097x.2009.00919.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND AND AIM Adrenaline, administered locally by microdialysis in skeletal muscle, causes vasoconstriction around the microdialysis catheter. This is contrary to the vasodilation that normally occurs when adrenaline is infused intravenously or intra-arterially. The hypothesis was tested that vasoconstriction, measured by microdialysis, would not occur with two interventions causing increased plasma levels of adrenaline, mental stress and intravenous adrenaline infusion (0.1 nmol kg(-1) min(-1)). METHODS Twenty-four men (27 +/- 1.6 years) underwent these interventions. Blood flow was determined by the microdialysis ethanol technique and (133)Xe clearance (gastrocnemius muscle, medial head) and by venous occlusion plethysmography (calf). RESULTS The ethanol outflow/inflow ratio, which is inversely related to blood flow, decreased to 92.0 +/- 3.4% of basal, P = 0.014 (mean +/- SEM, n = 16) during the mental stress test, but increased to 108.3 +/- 2.2% of basal, P = 0.001 (n = 16) during the adrenaline infusion. The latter increase was abolished when adrenaline was infused during alpha-receptor blockade by phentolamine. On the contrary, by (133)Xe clearance and venous occlusion plethysmography, blood flow increased during both interventions; 2.0-1.7-fold (mental stress) and 1.3-1.4-fold (adrenaline infusion), respectively, P<0.05. CONCLUSION Adrenaline causes vasoconstriction in skeletal muscle when blood flow is measured with the microdialysis ethanol technique, irrespective of the mode of administration. The discrepant blood flow result obtained with the microdialysis ethanol technique might, at least partly, be explained by differential diffusion properties of ethanol and (133)Xe. An additional or alternative explanation might be that an inserted microdialysis catheter shifts the balance of vasoconstrictor and vasodilator effects of adrenaline in skeletal muscle.
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Affiliation(s)
- U Widegren
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
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19
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Flechtner-Mors M, Jenkinson CP, Alt A, Adler G, Ditschuneit HH. Metabolism in adipose tissue in response to citalopram and trimipramine treatment--an in situ microdialysis study. J Psychiatr Res 2008; 42:578-86. [PMID: 17692337 DOI: 10.1016/j.jpsychires.2007.06.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2007] [Revised: 05/29/2007] [Accepted: 06/05/2007] [Indexed: 11/21/2022]
Abstract
The intake of antidepressants is often accompanied by weight gain. Antidepressants may influence lipid and carbohydrate metabolism that can result in metabolic changes and obesity. We investigated the effect of citalopram and trimipramine on interstitial glycerol, glucose and lactate concentration and blood flow in subcutaneous adipose tissue of obese subjects by means of the microdialysis technique. In addition, the effect of stimulation with norepinephrine on metabolic response was investigated. Each subject was compared to a control subject matched for BMI and age. Each group comprised 10 subjects. Circulating plasma triglyceride concentrations were higher in drug-treated groups. In subcutaneous adipose tissue, microdialysis experiments revealed a higher and prolonged glycerol release in the presence of norepinephrine, but not under basal conditions. In citalopram treated subjects, basal glucose and lactate concentrations were higher compared with controls or with the trimipramine treated group. Local administration of norepinephrine induced a decrease in glucose levels and an increase in lactate levels, but without significant differences between groups. Local adipose tissue blood flow decreased in control groups following norepinephrine application, but remained constant in the antidepressant groups. In conclusion, citalopram and trimipramine affected glucose and lipid metabolism in adipose tissue and resulted in enhanced release of glycerol and free fatty acids into the circulation.
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Affiliation(s)
- M Flechtner-Mors
- Department of Internal Medicine, University Ulm, Robert-Koch-Strasse 8, D-89081 Ulm, Germany.
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20
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Hutchinson DS, Summers RJ, Gibbs ME. Energy metabolism and memory processing: role of glucose transport and glycogen in responses to adrenoceptor activation in the chicken. Brain Res Bull 2008; 76:224-34. [PMID: 18498935 DOI: 10.1016/j.brainresbull.2008.02.019] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2007] [Revised: 01/22/2008] [Accepted: 02/11/2008] [Indexed: 11/28/2022]
Abstract
From experiments using a discriminated bead task in young chicks, we have defined when and where adrenoceptors (ARs) are involved in memory modulation. All three ARs subtypes (alpha(1)-, alpha(2)- and beta-ARs) are found in the chick brain and in regions associated with memory. Glucose and glycogen are important in the role of memory consolidation in the chick since increasing glucose levels improves memory consolidation while inhibiting glucose transporters (GLUTs) or glycogen breakdown inhibits memory consolidation. The selective beta(3)-AR agonist CL316243 enhances memory consolidation by a glucose-dependent mechanism and the administration of the non-metabolized glucose analogue 2-deoxyglucose reduces the ability of CL316243 to enhance memory. Agents that reduce glucose uptake by GLUTs and its incorporation into the glycolytic pathway also reduce the effectiveness of CL316243, but do not alter the dose-response relationship to the beta(2)-AR agonist zinterol. However, beta(2)-ARs do have a role in memory related to glycogen breakdown and inhibition of glycogenolysis reduces the ability of zinterol to enhance memory. Both beta(2)- and beta(3)-ARs are found on astrocytes from chick forebrain, and the actions of beta(3)-ARs on glucose uptake, and beta(2)-ARs on the breakdown of glycogen is consistent with an effect on astrocytic metabolism at the time of memory consolidation 30 min after training. We have shown that both beta(2)- and beta(3)-ARs can increase glucose uptake in chick astrocytes but do so by different mechanisms. This review will focus on the role of ARs on memory consolidation and specifically the role of energy metabolism on AR modulation of memory.
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Affiliation(s)
- Dana S Hutchinson
- Department of Pharmacology, Monash University, Clayton, Victoria 3800, Australia.
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21
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Murashita M, Kusumi I, Hosoda H, Kangawa K, Koyama T. Acute administration of clozapine concurrently increases blood glucose and circulating plasma ghrelin levels in rats. Psychoneuroendocrinology 2007; 32:777-84. [PMID: 17629416 DOI: 10.1016/j.psyneuen.2007.05.007] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2006] [Revised: 04/26/2007] [Accepted: 05/07/2007] [Indexed: 11/20/2022]
Abstract
OBJECTIVE Among antipsychotics, clozapine ranks highest in terms of the risk for weight gain and developing diabetes. However, the mechanism by which clozapine induces weight gain and diabetes remains unclear. The aim of this study was to determine the mechanism of clozapine-induced weight gain and hyperglycemia, and to clarify whether clozapine-induced hyperglycemia results from impairment of the system regulating appetite. METHODS Circulatory glucose, insulin, leptin and ghrelin levels were analyzed after acute administration of clozapine in rats. Clozapine (10 mg/kg) or a vehicle was injected intraperitoneally and blood samples were collected at 0, 15, 30, and 60 min after the injection. Clozapine (5, 10 or 20 mg/kg) or the vehicle was given, and blood samples were collected at 30 min after the injection. Since clozapine has receptor affinity for multiple neurotransmitters, selective antagonists of it, including dopamine, serotonin, alpha-adrenergic, muscarine and histamine were administered to clarify the pathway of clozapine-induced blood glucose and changes in plasma ghrelin. RESULTS Clozapine administration increased the blood glucose level at all time points (p<0.05) compared to controls. Plasma ghrelin was elevated at 30 min (p=0.0124) and 60 min (p=0.00152). Blood glucose was increased in rats given 5 (p=0.0344), 10 (p<0.0001), or 20 mg/kg (p<0.0001) clozapine, while plasma ghrelin was increased in rats treated with 10 mg/kg (p=0.0009) or 20 mg/kg (p=0.0059) clozapine. Blood glucose was increased in rats treated with a selective alpha1-adrenergic receptor antagonist (p<0.0001), while plasma ghrelin was significantly increased in rats given a selective alpha1- (p=0.025) or alpha2-adrenergic receptor antagonist (p=0.0003). CONCLUSIONS Clozapine impairs glucose metabolism and the appetite-regulation system. Clozapine increases blood glucose independent of insulin. The antagonistic action of alpha-adrenergic receptors is one of the mechanisms that induces both hyperglycemia and elevation of ghrelin.
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Affiliation(s)
- Mari Murashita
- Department of Psychiatry, Hokkaido University Graduate School of Medicine, Kita-15, Nishi-7, Kita-ku, Sapporo 060-8638, Japan.
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22
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Li Y, Peris J, Zhong L, Derendorf H. Microdialysis as a tool in local pharmacodynamics. AAPS JOURNAL 2006; 8:E222-35. [PMID: 16796373 PMCID: PMC3231563 DOI: 10.1007/bf02854892] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
In many cases the clinical outcome of therapy needs to be determined by the drug concentration in the tissue compartment in which the pharmacological effect occurs rather than in the plasma. Microdialysis is an in vivo technique that allows direct measurement of unbound tissue concentrations and permits monitoring of the biochemical and physiological effects of drugs throughout the body. Microdialysis was first used in pharmacodynamic research to study neurotransmission, and this remains its most common application in the field. In this review, we give an overview of the principles, techniques, and applications of microdialysis in pharmacodynamic studies of local physiological events, including measurement of endogenous substances such as acetylcholine, catecholamines, serotonin, amino acids, peptides, glucose, lactate, glycerol, and hormones. Microdialysis coupled with systemic drug administration also permits the more intensive examination of the pharmacotherapeutic effect of drugs on extracellular levels of endogenous substances in peripheral compartments and blood. Selected examples of the physiological effects and mechanisms of action of drugs are also discussed, as are the advantages and limitations of this method. It is concluded that microdialysis is a reliable technique for the measurement of local events, which makes it an attractive tool for local pharmacodynamic research.
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Affiliation(s)
- Yanjun Li
- />Department of Pharmaceutics, University of Florida, PO Box 100494, College of Pharmacy, 32610 Gainesville, FL
| | - Joanna Peris
- />Department of Pharmacodynamics, College of Pharmacy, University of Florida, 32610 Gainesville, FL
| | - Li Zhong
- />Department of Pediatrics, College of Medicine, University of Florida, 32610 Gainesville, FL
| | - Hartmut Derendorf
- />Department of Pharmaceutics, University of Florida, PO Box 100494, College of Pharmacy, 32610 Gainesville, FL
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