DOCSLIB.ORG

A443.Full.Pdf

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A443.Full.Pdf INTEGRATED PHYSIOLOGY—INSULINCATEGORY SECRETION IN VIVO 1719-P INTEGRATED PHYSIOLOGY—INSULIN SECRETION Glucose-Induced Extracellular Matrix Production is Negatively IN VIVO Regulated by Extracellular Signal Regulated Kinase 5 (ERK5) YUEXIU WU, BIAO FENG, SHALI CHEN, SUBRATA CHAKRABARTI, London, ON, Canada Increased extracellular matrix protein production is a characteristic fea- Guided Audio Tour: Genetic and Human Metabolic Predictors of Diabetes ture of diabetic complications. Fibronectin (FN), a key extracellular matrix (Posters 1721-P to 1728-P), see page 17. protein is known to be upregulated in diabetes. ERK5 plays a critical role in cardiovascular development and in maintaining endothelial cell integrity. The aim of the study is to investigate the regulation of ERK5 signaling on & 1721-P glucose-induced FN overproduction.Human microvascular endothelial cells Mexican American Subjects With Impaired Fasting Glucose (IFG) were used. FN mRNA and protein levels were measured using ELISA and are Characterized by Hepatic and Adipocyte Insulin Resistance and real-time PCR respectively. Transforming growth factor beta 1(TGF`1) ex- Beta Cell Dysfunction pression and Smad2 proteins were investigated. Constitutively active MEK5 RUTH ARYA, ZANDRA PEREZ-CADENA, ANDREA HANSIS-DIARTE, DEIDRE WIN- (CAMEK5) adenovirus was transducted to upregulate ERK5 signaling. ERK5 NIER, LAUREN CORTEZ, RALPH DEFRONZO, DEVJIT TRIPATHY, CHRISTOPHER siRNA and dominant negative MEK5 (DNMEK5) transfections were used JENKINSON, San Antonio, TX to downregulate ERK5.Glucose caused a dose dependent increase in FN The aim of the current study was to characterize the metabolic defects production. Such increase was associated with upregulation of TGF`1 and associated with prediabetic states IFG and impaired glucose tolerance (IGT). Smad2 phosphorylation. ERK5 expression peaked at 24 hrs. Signifi cant de- We compared adipocyte, hepatic and whole body insulin resistance and beta crease of basal and glucose induced increased FN mRNA and protein levels cell function in subjects with normal glucose tolerance NGT n=36 age 46±2 were observed after CAMEK5 transduction. In contrast, ERK5 siRNA and BMI 30±1, IFG n=30 age 47±2 BMI 33±1, IGT n=20 age 49±3 BMI 34±1, IFG/ DNMEK5 treatment led to an increase of FN synthesis. Moreover, West- IGT n=36 age 49±3 BMI 34±1, T2D n=81 age 58±1 BMI 35±1). Indices of in- ern blot analysis showed that phosphorylated Smad2 was suppressed by sulin secretion and insulin sensitivity were derived from plasma glucose, CAMEK5 transduction with or without glucose treatment. On the other hand insulin and FFA concentrations during the OGTT and from hyperinsulinemic siERK5 transfection enhanced TGF`1mRNA expression. Furthermore, we in- euglycemic clamp (80/mU/m2/min) with indirect calorimetry and tritiated vestigated neurotrophins, eg. nerve growth factor (NGF) and brain-derived glucose infusion (non-diabetics, n=54) to measure hepatic glucose produc- neurotrophic factor (BNDF). Both are known upstream regulators of ERK5. tion. Adipocyte IR (AR) was the product of fasting FFA and fasting insulin. IFG The alterations of neurotrophins paralleled that of ERK5. Exogenous NGF subjects had similar whole body glucose uptake but higher hepatic insulin re- supplementation resulted in elevated phosphorylated and total ERK5 with or sistance (BGP x Fasting insulin) vs NGT (21.2±4 vs 7.6±1 mg/kg/min, p<0.05). without glucose treatment.Taken together, our experiments demonstrated a Whole body glucose disposal (skeletal muscle) was lower in subjects with novel mechanism of FN regulation under high glucose conditions. Decreased IFG/IGT primarily due to reduced non-oxidative glucose metabolism. Plasma ERK5 signaling contributes to glucose-induced FN overproduction. fasting FFA and AR progressively increased from NGT to IFG to IFG/IGT and Supported by: Canadian Diabetes Association DM. Adipocyte IR correlated with whole body glucose disposal (r=-0.621, p<0.005), hepatic insulin resistance (r=0.766, p<0.005), insulin secretion/ insulin resistance (disposition) index 6I0-120/6G0-120 X MI (r=-0.248, p=0.01) 1720-P and the non-oxidative glucose disposal during the insulin clamp (r=-0.361, Exenatide Ameliorates Insulin Resistance by Upregulating SIRT1 p=0.03). Compared to NGT subjects the disposition index (6I0-120/6G0-120 x MI) Expression of Adipose Tissue in db/db Mice was reduced by 18%, 68%, 80% in IFG, IGT, and combined IFG/IGT respec- ZONGLAN CHEN, HUIMIN GU, FEN XU, JINHUA YAN, HUA LIANG, JIANPING tively. In conclusion subjects with IFG are characterized by hepatic insulin WENG, Guangzhou, China resistance while those with IGT primarily have skeletal muscle insulin resis- Although Exenatide can improve insulin sensitivity of obesity and type 2 tance and are characterized by marked beta cell dysfunction. Therapeutic diabetes, the underlying mechanisms are still poorly understood. Growing interventions to preserve beta cell function should be started early. evidence suggests that SIRT1 has a positive role in the metabolic pathway through its direct or indirect involvement in insulin signaling. In this study, we investigated the regulation of Exenatide on SIRT1 expression in white adipose tissue of db/db mice. The 7-8 weeks male db/db mice and their & 1722-P heterozygous were divided into 3 groups of 10 animals each as follows: NC Insulin Sensitivity, Insulin Secretion and Disposition Index in Per- group (db/m mice, normal control), DM group (db/db mice), EX group (db/ sons With Normal and “Pre-Diabetic” HbA1c Levels: The Pathobiol- db mice treated with Exenatide 24nmol/kg/d for 8 weeks). Intraperitoneal ogy of Prediabetes in A Biracial Cohort (POP-ABC) Study insulin tolerance test (IPITT) indicated Exenatide could improve insulin sen- CHIMAROKE EDEOGA, SOTONTE EBENIBO, SAMUEL DAGOGO-JACK, Memphis, sitivity and lower fasting glucose levels signifi cantly in db/db mice. Western TN blotting analysis demonstrated that DM group had decreased expressions of An A1c range of 5.7-6.4% has been suggested for the diagnosis of predia- SIRT1, IRS1 and increased expression of p-JNK as compared with NC group. betes. In this report, we compared metabolic data in persons with normal All of these changes were attenuated or reversed when the diabetic mice (N=189) or “prediabetic”(N=98) status based on A1c. We studied 287 nondia- were treated with Exenatide. Our data suggested that Exenatide treatment betic adult offspring (147 black, 140 white) of type 2 diabetes (T2DM) par- ameliorated insulin resistance in db/db mice potentially through regulating ents enrolled in POP-ABC, a study of incident dysglycemia among offspring SIRT1-p-JNK-IRS1 axis. of T2DM parents. Their mean (+ SD) age was 44.2 + 10.6 y and BMI was 30.2 + 7.25 kg/m2. Baseline measurements included anthropometrics, 75-g OGTT and A1c level, followed by IVGTT and DEXA within 3 months of enrollment. Insulin action (M) was measured using euglycemic clamp, and beta-cell func- tion was assessed using acute insulin response (AIR) during IVGTT. The dis- Obesity position index (DI) was calculated as the product of AIR and M. Basal homeo- POSTERS stasis was assessed by calculating HOMA-IR and HOMA-B. Compared to the normal controls (A1c < 5.7%), subjects with “prediabetic”A1c levels (5.7- Integrated Physiology/ 6.4%) were older (47.9 + 9.2 (SD), P=0.0004), and had higher fasting glucose (92.2 + 6.45 vs. 90.2 + 7.25 mg/dl, P=0.011), BMI (31.5 +7.97 vs. 29.2 + 13.2 kg/m2, P=0.03), total body fat (P=0.02) and trunk fat mass (P=0.016). How- ever, there were no signifi cant differences between the two groups with regard to HOMA-IR, HOMA-B, AIR, M value or DI in African Americans or Supported by: Program for Changjiang Scholars and Innovative Research Team Caucasiand (Fig 1). We conclude that an A1c range of 5.7-6.4% is associated with increased adiposity, but does not predict established glucoregulatory impairments that enable distinction from persons with lower A1c values. ADA-Funded Research & Guided Audio Tour poster For author disclosure information, see page 797. A443 INTEGRATED PHYSIOLOGY—INSULINCATEGORY SECRETION IN VIVO false positive fi ndings. Fortyfi ve SNPs, selected to cover over 90% of com- mon genetic variability, were genotyped in 8 MODY (HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, KLF11, CEL) and 2 neonatal diabetes (NDM) (KCNJ11, ABCC8) genes. Allelic variants of 4 SNPs (rs1303722 and rs882019 of GCK, rs7310409 of HNF1A and rs5219 of KCNJ11, the latter being a known type 2 diabetes risk variant) exerted independent signifi cant effects on DC of beta- cell function (p=0.007-0.03). Allelic variants of 5 other SNPs (rs2869084 and rs6031544 of HNF4A, rs10774580 of HNF1A, rs1801262 of NEUROD1, and rs7129639 of ABCC8) were found to infl uence signifi cantly PC of beta-cell function (p=0.001-0.04). Only 1 (rs6721191 of KLF11) out of 45 SNPs was asso- ciated to insulin sensitivity (p=0.047). In multivariate models, combining GCK, HNF1A and KCNJ11 SNPs accounted for ~2,5% of DC of beta-cell function, whereas combining HNF4A, HNF1A, NEUROD1 and ABCC8 SNPs accounted Supported by: NIH-NIDDK for ~3.6% of PC of beta-cell function. We conclude that common variability of MODY and NDM genes signifi cantly affects beta cell function in patients with type 2 diabetes, thereby potentially playing a role in the pathophysiol- & 1723-P ogy and/or the “metabolic prognosis” of the disease. Short Term Mild Hyperglycemia Improves Oral Glucose Disposal Supported by: European Foundation for the Study of Diabetes/Novartis Grant and Ƶ-Cell Function in Subjects With Impaired Glucose Tolerance (IGT) LORENA A. WRIGHT, KRISTINA M. UTZSCHNEIDER, JENNY TONG, SEDA SUVAG, & 1725-P STEVEN E. KAHN, Seattle, WA, Cincinatti, OH Mutations in ABCA1 and Enhanced Ƶ-cell Secretory Capacity in Hu- Mild 24 h hyperglycemia improves insulin sensitivity, `-cell function and mans: Preliminary Results glucose disposal in subjects with normal glucose tolerance.
Load more

Recommended publications
  • • Our Bodies Make All the Cholesterol We Need. • 85 % of Our Blood
    • Our bodies make all the cholesterol we need. • 85 % of our blood cholesterol level is endogenous • 15 % = dietary from meat, poultry, fish, seafood and dairy products. • It's possible for some people to eat foods high in cholesterol and still have low blood cholesterol levels. • Likewise, it's possible to eat foods low in cholesterol and have a high blood cholesterol level SYNTHESIS OF CHOLESTEROL • LOCATION • All tissues • Liver • Cortex of adrenal gland • Gonads • Smooth endoplasmic reticulum Cholesterol biosynthesis and degradation • Diet: only found in animal fat • Biosynthesis: primarily synthesized in the liver from acetyl-coA; biosynthesis is inhibited by LDL uptake • Degradation: only occurs in the liver • Cholesterol is only synthesized by animals • Although de novo synthesis of cholesterol occurs in/ by almost all tissues in humans, the capacity is greatest in liver, intestine, adrenal cortex, and reproductive tissues, including ovaries, testes, and placenta. • Most de novo synthesis occurs in the liver, where cholesterol is synthesized from acetyl-CoA in the cytoplasm. • Biosynthesis in the liver accounts for approximately 10%, and in the intestines approximately 15%, of the amount produced each day. • Since cholesterol is not synthesized in plants; vegetables & fruits play a major role in low cholesterol diets. • As previously mentioned, cholesterol biosynthesis is necessary for membrane synthesis, and as a precursor for steroid synthesis including steroid hormone and vitamin D production, and bile acid synthesis, in the liver. • Slightly less than half of the cholesterol in the body derives from biosynthesis de novo. • Most cells derive their cholesterol from LDL or HDL, but some cholesterol may be synthesize: de novo.
    [Show full text]
  • Cholesterol Metabolites 25-Hydroxycholesterol and 25-Hydroxycholesterol 3-Sulfate Are Potent Paired Regulators: from Discovery to Clinical Usage
    H OH metabolites OH Review Cholesterol Metabolites 25-Hydroxycholesterol and 25-Hydroxycholesterol 3-Sulfate Are Potent Paired Regulators: From Discovery to Clinical Usage Yaping Wang 1, Xiaobo Li 2 and Shunlin Ren 1,* 1 Department of Internal Medicine, McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA 23249, USA; [email protected] 2 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; [email protected] * Correspondence: [email protected]; Tel.: +1-(804)-675-5000 (ext. 4973) Abstract: Oxysterols have long been believed to be ligands of nuclear receptors such as liver × recep- tor (LXR), and they play an important role in lipid homeostasis and in the immune system, where they are involved in both transcriptional and posttranscriptional mechanisms. However, they are increas- ingly associated with a wide variety of other, sometimes surprising, cell functions. Oxysterols have also been implicated in several diseases such as metabolic syndrome. Oxysterols can be sulfated, and the sulfated oxysterols act in different directions: they decrease lipid biosynthesis, suppress inflammatory responses, and promote cell survival. Our recent reports have shown that oxysterol and oxysterol sulfates are paired epigenetic regulators, agonists, and antagonists of DNA methyl- transferases, indicating that their function of global regulation is through epigenetic modification. In this review, we explore our latest research of 25-hydroxycholesterol and 25-hydroxycholesterol 3-sulfate in a novel regulatory mechanism and evaluate the current evidence for these roles. Citation: Wang, Y.; Li, X.; Ren, S. Keywords: oxysterol sulfates; oxysterol sulfation; epigenetic regulators; 25-hydroxysterol; Cholesterol Metabolites 25-hydroxycholesterol 3-sulfate; 25-hydroxycholesterol 3,25-disulfate 25-Hydroxycholesterol and 25-Hydroxycholesterol 3-Sulfate Are Potent Paired Regulators: From Discovery to Clinical Usage.
    [Show full text]
  • Genetic Deletion of Abcc6 Disturbs Cholesterol Homeostasis in Mice Bettina Ibold1, Janina Tiemann1, Isabel Faust1, Uta Ceglarek2, Julia Dittrich2, Theo G
    www.nature.com/scientificreports OPEN Genetic deletion of Abcc6 disturbs cholesterol homeostasis in mice Bettina Ibold1, Janina Tiemann1, Isabel Faust1, Uta Ceglarek2, Julia Dittrich2, Theo G. M. F. Gorgels3,4, Arthur A. B. Bergen4,5, Olivier Vanakker6, Matthias Van Gils6, Cornelius Knabbe1 & Doris Hendig1* Genetic studies link adenosine triphosphate-binding cassette transporter C6 (ABCC6) mutations to pseudoxanthoma elasticum (PXE). ABCC6 sequence variations are correlated with altered HDL cholesterol levels and an elevated risk of coronary artery diseases. However, the role of ABCC6 in cholesterol homeostasis is not widely known. Here, we report reduced serum cholesterol and phytosterol levels in Abcc6-defcient mice, indicating an impaired sterol absorption. Ratios of cholesterol precursors to cholesterol were increased, confrmed by upregulation of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase (Hmgcr) expression, suggesting activation of cholesterol biosynthesis in Abcc6−/− mice. We found that cholesterol depletion was accompanied by a substantial decrease in HDL cholesterol mediated by lowered ApoA-I and ApoA-II protein levels and not by inhibited lecithin-cholesterol transferase activity. Additionally, higher proprotein convertase subtilisin/kexin type 9 (Pcsk9) serum levels in Abcc6−/− mice and PXE patients and elevated ApoB level in knockout mice were observed, suggesting a potentially altered very low-density lipoprotein synthesis. Our results underline the role of Abcc6 in cholesterol homeostasis and indicate impaired cholesterol metabolism as an important pathomechanism involved in PXE manifestation. Mutations in the adenosine triphosphate-binding cassette transporter C6 (ABCC6) gene are responsible for pseudoxanthoma elasticum (PXE), a metabolic disease, hallmarked by a progressive elastic fber calcifcation of the skin, eyes and cardiovascular system.
    [Show full text]
  • The Impact of the Nonpeptide Corticotropin-Releasing Hormone Antagonist Antalarmin on Behavioral and Endocrine Responses to Stress*
    0013-7227/99/$03.00/0 Vol. 140, No. 1 Endocrinology Printed in U.S.A. Copyright © 1999 by The Endocrine Society The Impact of the Nonpeptide Corticotropin-Releasing Hormone Antagonist Antalarmin on Behavioral and Endocrine Responses to Stress* TERRENCE DEAK, KIEN T. NGUYEN, ANDREA L. EHRLICH, LINDA R. WATKINS, ROBERT L. SPENCER, STEVEN F. MAIER, JULIO LICINIO, MA-LI WONG, GEORGE P. CHROUSOS, ELIZABETH WEBSTER, AND PHILIP W. GOLD Department of Psychology (T.D., K.T.N., A.L.E., L.R.W., R.L.S., S.F.M.), University of Colorado, Boulder, Colorado 80309-0345; Clinical Neuroendocrinology Branch (J.L., M.-L.W., P.W.G.), National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-1284; and Developmental Neuroendocrinology Branch (G.P.C., E.W.), National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1284 ABSTRACT Furthermore, because rats previously exposed to inescapable shock The nonpeptide CRH antagonist antalarmin has been shown to (IS; 100 shocks, 1.6 mA, 5 sec each), demonstrate enhanced fear block both behavioral and endocrine responses to CRH. However, it’s conditioning, we investigated whether this effect would be blocked by potential activity in blunting behavioral and endocrine sequelae of antalarmin. Antalarmin (20 mg/kgz2 ml ip) impaired both the induc- stressor exposure has not been assessed. Because antagonism of cen- tion and expression of conditioned fear. In addition, antalarmin tral CRH by a-helical CRH attenuates conditioned fear responses, we blocked the enhancement of fear conditioning produced by prior ex- sought to test antalarmin in this regard.
    [Show full text]
  • Adverse Effects of Stress on Drug Addiction
    Making a bad thing worse: adverse effects of stress on drug addiction Jessica N. Cleck, Julie A. Blendy J Clin Invest. 2008;118(2):454-461. https://doi.org/10.1172/JCI33946. Review Series Sustained exposure to various psychological stressors can exacerbate neuropsychiatric disorders, including drug addiction. Addiction is a chronic brain disease in which individuals cannot control their need for drugs, despite negative health and social consequences. The brains of addicted individuals are altered and respond very differently to stress than those of individuals who are not addicted. In this Review, we highlight some of the common effects of stress and drugs of abuse throughout the addiction cycle. We also discuss both animal and human studies that suggest treating the stress- related aspects of drug addiction is likely to be an important contributing factor to a long-lasting recovery from this disorder. Find the latest version: https://jci.me/33946/pdf Review series Making a bad thing worse: adverse effects of stress on drug addiction Jessica N. Cleck and Julie A. Blendy Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. Sustained exposure to various psychological stressors can exacerbate neuropsychiatric disorders, including drug addiction. Addiction is a chronic brain disease in which individuals cannot control their need for drugs, despite negative health and social consequences. The brains of addicted individuals are altered and respond very differently to stress than those of individuals who are not addicted. In this Review, we highlight some of the common effects of stress and drugs of abuse throughout the addiction cycle.
    [Show full text]
  • Mechanism of Satellite Cell Regulation by Myokines
    J Phys Fitness Sports Med, 6 (5): 311-316 (2017) DOI: 10.7600/jpfsm.6.311 JPFSM: Review Article Mechanism of satellite cell regulation by myokines Yasuro Furuichi* and Nobuharu L. Fujii Department of Health Promotion Sciences, Graduate School of Human Health Sciences, Tokyo Metropolitan University, 1-1 Minami-Osawa, Hachioji, Tokyo 193-0397, Japan Received: July 19, 2017 / Accepted: August 7, 2017 Abstract Skeletal muscle stem cells, known as satellite cells, participate in postnatal skeletal muscle growth, regeneration, and hypertrophy. They are quiescent in the resting state, but are activated after muscle injury, and subsequently replicate and fuse into existing myofibers. The behavior of satellite cells during muscle regeneration is regulated by extrinsic factors, such as the extracellular matrix, mechanical stimuli, and soluble factors. Myokines, muscle-derived secretory factors, are important regulators of satellite cell activation, proliferation, and differen- tiation. It is well known that muscle injury induces the release of various growth factors from myofibers, and these growth factors affect satellite cells. It has recently been shown that myo- kines secreted from myofibers without cell damage also regulate satellite cell functions. Here, we summarize myokines with known roles in the regulation of satellite cells and the mecha- nism underlying this regulatory process. Keywords : secretion, myogenesis, muscle regeneration regulation, but there are also molecules related to muscle Introduction regeneration or plasticity. In this review, we introduce the Skeletal muscle is a unique tissue that has a remarkable reported myokines involved in the regulation of satellite ability to regenerate after injury. In response to tissue cell behavior and its molecular mechanism.
    [Show full text]
  • WO 2015/072852 Al 21 May 2015 (21.05.2015) P O P C T
    (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/072852 Al 21 May 2015 (21.05.2015) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 36/84 (2006.01) A61K 31/5513 (2006.01) kind of national protection available): AE, AG, AL, AM, A61K 31/045 (2006.01) A61P 31/22 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, A61K 31/522 (2006.01) A61K 45/06 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (21) International Application Number: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, PCT/NL20 14/050780 KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, (22) International Filing Date: MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, 13 November 2014 (13.1 1.2014) PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (25) Filing Language: English TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (26) Publication Language: English (84) Designated States (unless otherwise indicated, for every (30) Priority Data: kind of regional protection available): ARIPO (BW, GH, 61/903,430 13 November 2013 (13. 11.2013) US GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, (71) Applicant: RJG DEVELOPMENTS B.V.
    [Show full text]
  • Neuropeptides: Implications for Alcoholism
    Journal of Neurochemistry, 2004, 89, 273–285 doi:10.1111/j.1471-4159.2004.02394.x REVIEW Neuropeptides: implications for alcoholism Michael S. Cowen*, , Feng Chen*, and Andrew J. Lawrence*, *The Howard Florey Institute, University of Melbourne, VIC 3010, Australia Department of Pharmacology, Monash University, VIC 3800 Australia Abstract (CRF), urocortin I and neuropeptide Y (NPY) in deleterious The role of neuromodulatory peptides in the aetiology of and excessive alcohol consumption, focussing on specific alcoholism has been relatively under-explored; however, the brain regions, in particular the central nucleus of the development of selective ligands for neuropeptide receptors, amygdala, that appear to be implicated in the pathophysi- the characterization and cloning of receptors, and the ology of alcoholism. The review also outlines potential development of transgenic mouse models have greatly directions for further research to clarify neuropeptide facilitated this analysis. The present review considers the involvement in neuromodulation within discrete brain nuclei most recent preclinical evidence obtained from animal pertinent to behavioural patterns. models for the role of two of the opioid peptides, namely J. Neurochem. (2004) 89, 273–285. b-endorphin and enkephalin; corticotropin-releasing factor Alcohol causes as much, if not more death and disabilityas analysis. However, drugs that interact with neuropeptide measles, malaria, tobacco or illegal drugs (World Health systems have great potential in the pharmacotherapy of Organization, 2001) . In economic terms, alcohol abuse has alcoholism: witness the widespread (although somewhat less been estimated at US$167 billion per year; however, ‘in than satisfactory) use of the opioid antagonist naltrexone in human terms, the costs are incalculable’ (National Institute the treatment of alcoholism (O’Malley et al.
    [Show full text]
  • Physical Exercise and Myokines: Relationships with Sarcopenia and Cardiovascular Complications
    International Journal of Molecular Sciences Review Physical Exercise and Myokines: Relationships with Sarcopenia and Cardiovascular Complications Sandra Maria Barbalho 1,2,3,* , Uri Adrian Prync Flato 1,2 , Ricardo José Tofano 1,2, Ricardo de Alvares Goulart 1, Elen Landgraf Guiguer 1,2,3 , Cláudia Rucco P. Detregiachi 1 , Daniela Vieira Buchaim 1,4, Adriano Cressoni Araújo 1,2 , Rogério Leone Buchaim 1,5, Fábio Tadeu Rodrigues Reina 1, Piero Biteli 1, Daniela O. B. Rodrigues Reina 1 and Marcelo Dib Bechara 2 1 Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marilia (UNIMAR), Avenue Hygino Muzzy Filho, 1001, Marília 17525-902, São Paulo, Brazil; urifl[email protected] (U.A.P.F.); [email protected] (R.J.T.); [email protected] (R.d.A.G.); [email protected] (E.L.G.); [email protected] (C.R.P.D.); [email protected] (D.V.B.); [email protected] (A.C.A.); [email protected] (R.L.B.); [email protected] (F.T.R.R.); [email protected] (P.B.); [email protected] (D.O.B.R.R.) 2 School of Medicine, University of Marília (UNIMAR), Avenida Higino Muzzi Filho, 1001, Marília 17506-000, São Paulo, Brazil; [email protected] 3 Department of Biochemistry and Nutrition, Food Technology School, Marília 17525-902, São Paulo, Brazil 4 Medical School, University Center of Adamantina (UniFAI), Adamantina 17800-000, São Paulo, Brazil 5 Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo (FOB–USP), Alameda Doutor Octávio Pinheiro Brisolla, 9-75, Bauru 17012901, São Paulo, Brazil * Correspondence: [email protected]; Tel.: +55-14-99655-3190 Received: 6 May 2020; Accepted: 19 May 2020; Published: 20 May 2020 Abstract: Skeletal muscle is capable of secreting different factors in order to communicate with other tissues.
    [Show full text]
  • Potential PET Ligands for Imaging of Cerebral VPAC and PAC Receptors: Are NonPeptide Small Molecules Superior to Peptide Compounds?
    World Journal of Neuroscience, 2015, 5, 364384 Published Online November 2015 in SciRes. http://www.scirp.org/journal/wjns http://dx.doi.org/10.4236/wjns.2015.55036 Potential PET Ligands for Imaging of Cerebral VPAC and PAC Receptors: Are NonPeptide Small Molecules Superior to Peptide Compounds? Margit Pissarek INM5, Nuclear Chemistry, Institute of Neurosciences and Medicine, Research Centre Jülich, Jülich, Germany Received 15 August 2015; accepted 13 November 2015; published 17 November 2015 Copyright © 2015 by author and Scientific Research Publishing Inc. This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/ Abstract Pituitary adenylate cyclase activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) have been known for decades to mediate neuroendocrine and vasodilative actions via Gprotein coupled receptors of Class B. These are targets of imaging probes for positron emission tomogra phy (PET) or single photon emission tomography (SPECT) in tumor diagnostics and tumor grading. However, they play only a subordinate role in the development of tracers for brain imaging. Diffi culties in development of nonpeptide ligands typical for cerebral receptors of PACAP and VIP are shared by all members of Class B receptor family. Essential landmarks have been confirmed for understanding of structural details of Class B receptor molecular signalling during the last five years. High relevance in the explanation of problems in ligand development for these receptors is admitted to the large Nterminal ectodomain markedly different from Class A receptor binding sites and poorly suitable as orthosteric binding sites for the most smallmolecule compounds. The present study is focused on the recently available receptor ligands for PAC1, VPAC1 and VPAC2 receptors as well as potential smallmolecule lead structures suitable for use in PET or SPECT.
    [Show full text]
  • Role of Dorsal Medial Prefrontal Cortex Dopamine D1-Family Receptors in Relapse to High-Fat Food Seeking Induced by the Anxiogenic Drug Yohimbine
    Neuropsychopharmacology (2011) 36, 497–510 & 2011 American College of Neuropsychopharmacology. All rights reserved 0893-133X/11 $32.00 www.neuropsychopharmacology.org Role of Dorsal Medial Prefrontal Cortex Dopamine D1-Family Receptors in Relapse to High-Fat Food Seeking Induced by the Anxiogenic Drug Yohimbine 1 1 1 1 1 Sunila G Nair , Brittany M Navarre , Carlo Cifani , Charles L Pickens , Jennifer M Bossert and Yavin Shaham*,1 1 Behavioral Neuroscience Branch, NIDA/IRP/NIH/DHHS, Baltimore, MD, USA In humans, relapse to maladaptive eating habits during dieting is often provoked by stress. In rats, the anxiogenic drug yohimbine, which causes stress-like responses in both humans and nonhumans, reinstates food seeking in a relapse model. In this study, we examined the role of medial prefrontal cortex (mPFC) dopamine D1-family receptors, previously implicated in stress-induced reinstatement of drug seeking, in yohimbine-induced reinstatement of food seeking. We trained food-restricted rats to lever press for 35% high-fat pellets every other day (9–15 sessions, 3 h each); pellet delivery was accompanied by a discrete tone-light cue. We then extinguished operant responding for 10–16 days by removing the pellets. Subsequently, we examined the effect of yohimbine (2 mg/kg, i.p.) on reinstatement of food seeking and Fos (a neuronal activity marker) induction in mPFC. We then examined the effect of systemic injections of the D1-family receptor antagonist SCH23390 (10 mg/kg, s.c.) on yohimbine-induced reinstatement and Fos induction, and that of mPFC SCH23390 (0.5 and 1.0 mg/side) injections on this reinstatement.
    [Show full text]
  • G Protein-Coupled Receptors
    S.P.H. Alexander et al. The Concise Guide to PHARMACOLOGY 2015/16: G protein-coupled receptors. British Journal of Pharmacology (2015) 172, 5744–5869 THE CONCISE GUIDE TO PHARMACOLOGY 2015/16: G protein-coupled receptors Stephen PH Alexander1, Anthony P Davenport2, Eamonn Kelly3, Neil Marrion3, John A Peters4, Helen E Benson5, Elena Faccenda5, Adam J Pawson5, Joanna L Sharman5, Christopher Southan5, Jamie A Davies5 and CGTP Collaborators 1School of Biomedical Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK, 2Clinical Pharmacology Unit, University of Cambridge, Cambridge, CB2 0QQ, UK, 3School of Physiology and Pharmacology, University of Bristol, Bristol, BS8 1TD, UK, 4Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK, 5Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK Abstract The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/ 10.1111/bph.13348/full. G protein-coupled receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: ligand-gated ion channels, voltage-gated ion channels, other ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading.
    [Show full text]