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A1 Adenosine Receptor: Role in Diabetes and Obesity

Part of the Handbook of Experimental Pharmacology book series (HEP,volume 193)

Abstract

Adenosine mediates its diverse effects via four subtypes (A1, A2A, A2B and A3) of G-protein-coupled receptors. The A1 adenosine receptor (A1AR) subtype is the most extensively studied and is well characterized in various organ systems. The A1ARs are highly expressed in adipose tissue, and endogenous adenosine has been shown to tonically activate adipose tissue A1ARs. Activation of the A1ARs in adipocytes reduces adenylate cyclase and cAMP content and causes inhibition of lipolysis. The role of A1ARs in lipolysis has been well characterized by using several selective A1AR agonists as well as A1AR knockout mice. However, the contribution of A1ARs to the regulation of lipolysis in pathological conditions like insulin resistance, diabetes and dyslipidemia, where free fatty acids (FFA) play an important role, has not been well characterized. Pharmacological agents that reduce the release of FFA from adipose tissue and thus the availability of circulating FFA have the potential to be useful for insulin resistance and hyperlipidemia. Toward this goal, several selective and efficacious agonists of the A1ARs are now available, and some have entered early-phase clinical trials; however, none have received regulatory approval yet. Here we review the existing knowledge on the role of A1ARs in insulin resistance, diabetes and obesity, and the progress made in the development of A1AR agonists as antilipolytic agents, including the challenges associated with this approach.

Keywords

  • A1 Adenosine Receptor
  • Antilipolytic
  • Insulin Resistance
  • Diabetes
  • Obesity

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Fig. 1
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Fig. 3

Abbreviations

A1AR:

A1 Adenosine receptor

A2AAR:

A2A Adenosine receptor

A2BAR:

A2B Adenosine receptor

AR:

Adenosine receptor

ATGL:

Adipose triglyceride lipase

BMI:

Body mass index

cAMP:

Cyclic adenosine monophosphate

CCPA:

2-Chloro-N 6-cyclopentyladenosine

FFA:

Free fatty acids

GPCR:

G-protein-coupled receptor

HPIA:

Hydroxyphenylisopropyl adenosine

HSL:

Hormone-sensitive lipase

KO:

Knockout

NFkB:

Nuclear factor kappa beta

PIA:

Phenylisopropyladenosine

PI3:

Phosphoinositide 3

PKA:

Protein kinase A

PKC:

Protein kinase C

R-PIA:

N 6-(R)-Phenylisopropyladenosine

SPA:

N 6-(p-Sulfophenyl)adenosine

TG:

Triglycerides

VLDL-TG:

Very low density lipoprotein triglyceride

References

  • Ashton TD, Baker SP, Hutchinson SA, Scammells PJ (2008) N 6-Substituted C5-modified adenosines as A1 adenosine receptor agonists. Bioorg Med Chem 16:1861–1873

    CAS  PubMed  CrossRef  Google Scholar 

  • Baker SP, Scammells PJ, Belardinelli L (2000) Differential A(1)-adenosine receptor reserve for inhibition of cyclic AMP accumulation and G-protein activation in DDT(1) MF-2 cells. Br J Pharmacol 130:1156–1164

    CAS  PubMed  CrossRef  Google Scholar 

  • Barakat H, Davis J, Lang D, Mustafa SJ, McConnaughey MM (2006) Differences in the Expression of the adenosine A1 receptor in adipose tissue of obese black and white women. J Clin Endocrinol Met 91:1882–1886

    CAS  CrossRef  Google Scholar 

  • Bays H, Mandarino L, DeFronzo RA (2004) Role of the adipocyte, free fatty acids, and ectopic fat in pathogenesis of type 2 diabetes mellitus: peroxisomal proliferator-activated receptor agonists provide a rational therapeutic approach. J Clin Endocrinol Met 89:463–478

    CAS  CrossRef  Google Scholar 

  • Belardinelli L, Linden J, Berne RM (1989) The cardiac effects of adenosine. Prog Cardiovasc Dis 32:73–97

    CAS  PubMed  CrossRef  Google Scholar 

  • Berkich DA, Luthin DR, Woodard RL, Vannucci SJ, Linden J, LaNoue KF (1995) Evidence for regulated coupling of A1 adenosine receptors by phosphorylation in Zucker rats. Am J Physiol 268: E693–E704

    CAS  PubMed  Google Scholar 

  • Boden G (2001) Free fatty acids—the link between obesity and insulin resistance. Endocr Pract 7:44–51

    CAS  PubMed  Google Scholar 

  • Boden G (2002) Obesity and diabetes mellitus—how are they linked? West Indian Med J 51(Suppl 1):51–54

    PubMed  Google Scholar 

  • Boden G, She P, Mozzoli M, Cheung P, Gumireddy K, Reddy P, Xiang X, Luo Z, Ruderman N (2005) Free fatty acids produce insulin resistance and activate the proinflammatory nuclear factor-{kappa}b pathway in rat liver. Diabetes 54:3458–3465

    CAS  PubMed  CrossRef  Google Scholar 

  • Borglum JD, Vassaux G, Richelsen B, Gaillard D, Darimont C, Ailhaud G, Negrel R (1996) Changes in adenosine A1- and A2-receptor expression during adipose cell differentiation. Mol Cell Endocrinol 117:17–25

    CAS  PubMed  CrossRef  Google Scholar 

  • Brechler V, Pavoine C, Lotersztajn S, Garbarz E, Pecker F (1990) Activation of Na+/Ca+ exchange by adenosine in ewe heart sarcolemma is mediated by a pertussis toxin-sensitive G protein. J Biol Chem 265(28):16851–16855

    CAS  PubMed  Google Scholar 

  • Budohoski L, Challiss RA, McManus B, Newsholme EA (1984) Effects of analogues of adenosine and methyl xanthines on insulin sensitivity in soleus muscle of the rat. FEBS Lett 167:1–4

    CAS  PubMed  CrossRef  Google Scholar 

  • Butcher RW, Ho RJ, Meng HC, Sutherland EW (1965) Adenosine 3, 5-monophosphate in biological materials. II. The measurement of adenosine 3, 5-monophosphate in tissues and the role of the cyclic nucleotide in the lipolytic response of fat to epinephrine. J Biol Chem 240:4515–4523

    CAS  PubMed  Google Scholar 

  • Cappellacci L, Franchetti P, Vita P, Petrelli R, Lavecchia A, Costa B, Spinetti F, Martini C, Klotz KN, Grifantini M (2008) 5-Carbamoyl derivatives of 2-C-methyl-purine nucleosides as selective A1 adenosine receptor agonists: affinity, efficacy, and selectivity for A1 receptor from different species. Bioorg Med Chem 16:336–353

    CAS  PubMed  CrossRef  Google Scholar 

  • Carlson LA (2005) Nicotinic acid: the broad-spectrum lipid drug. A 50th anniversary review. J Intern Med 258:94–114

    CAS  PubMed  CrossRef  Google Scholar 

  • Cheng JT, Chi TC, Liu IM (2000) Activation of adenosine A1 receptors by drugs to lower plasma glucose in streptozotocin-induced diabetic rats. Auton Neurosci 83:127–133

    CAS  PubMed  CrossRef  Google Scholar 

  • Ciruela F, Saura C, Canela EI, Mallol J, Lluis C, Franco R (1997) Ligand-induced phosphorylation, clustering, and desensitization of A1 adenosine receptors. Mol Pharmacol 52:788–797

    CAS  PubMed  Google Scholar 

  • Cox BF, Clark KL, Perrone MH, Welzel GE, Greenland BD, Colussi DJ, Merkel LA (1997) Cardiovascular and metabolic effects of adenosine A1-receptor agonists in streptozotocin-treated rats. J Cardiovasc Pharmacol 29:417–426

    CAS  PubMed  CrossRef  Google Scholar 

  • Cristalli G, Franchetti P, Grifantini M, Vittori S, Klotz KN, Lohse MJ (1988) Adenosine receptor agonists: synthesis and biological evaluation of 1-deaza analogues of adenosine derivatives. J Med Chem 31:1179–1183

    CAS  PubMed  CrossRef  Google Scholar 

  • de Ligt RA, IJzerman AP (2002) Intrinsic activity at adenosine A1 receptors: partial and inverse agonism. Curr Pharm Des 8:2333–2344

    PubMed  CrossRef  Google Scholar 

  • Dhalla AK, Shryock JC, Shreeniwas R, Belardinelli L (2003) Pharmacology and therapeutic applications of A1 adenosine receptor ligands. Curr Top Med Chem 3:369–385

    CAS  PubMed  CrossRef  Google Scholar 

  • Dhalla AK, Wong MY, Wang WQ, Biaggioni I, Belardinelli L (2006) Tachycardia caused by A2A adenosine receptor agonists is mediated by direct sympathoexcitation in awake rats. JPET 316:695–702

    CAS  CrossRef  Google Scholar 

  • Dhalla A, Santikul M, Smith M, Wong MY, Shryock J, Belardinelli L (2007a) Anti-lipolytic activity of a novel partial A1 adenosine receptor agonist devoid of cardiovascular effects: Comparison with nicotinic acid. JPET 321:327–333

    CAS  CrossRef  Google Scholar 

  • Dhalla AK, Wong MY, Voshol PJ, Belardinelli L, Reaven GM (2007b) A1 adenosine receptor partial agonist lowers plasma FFA and improves insulin resistance induced by high-fat diet in rodents. Am J Physiol Endocrinol Metab 292:E1358–E1363

    CAS  PubMed  CrossRef  Google Scholar 

  • Dhalla AK, Santikul M, Chisholm JW, Belardinelli L, Reaven GM (2008) Comparison of the antilipolytic effects of an A1 adenosine receptor partial agonist in normal and diabetic rats. Diabetes Obes Metab 11:95–101

    PubMed  CrossRef  CAS  Google Scholar 

  • Dixon AK, Gubitz AK, Sirinathsinghji DJS, Richardson PJ, Freeman TC (1996) Tissue distribution of adenosine receptor mRNAs in the rat. Br J Pharmacol 118:1461–1468

    CAS  PubMed  Google Scholar 

  • Dobson JG Jr (1978) Reduction by adenosine of the isoproterenol-induced increase in cyclic adenosine 3, 5-monophosphate formation and glycogen phosphorylase activity in rat heart muscle. Circ Res 43:785–792

    CAS  PubMed  Google Scholar 

  • Dobson JG Jr (1983) Interaction between adenosine and inotropic interventions in guinea pig atria. Am J Physiol 245: H475–H480

    CAS  PubMed  Google Scholar 

  • Dobson JG Jr, Ordway RW, Fenton RA (1986) Endogenous adenosine inhibits catecholamine contractile responses in normoxic hearts. Am J Physiol 251:H455–H462

    CAS  PubMed  Google Scholar 

  • Dole VP (1961) Effect of nucleic acid metabolites on lipolysis in adipose tissue. J Biol Chem 236:3125–3130

    CAS  PubMed  Google Scholar 

  • Dong Q, Ginsberg HN, Erlanger BF (2001) Overexpression of the A1 adenosine receptor in adipose tissue protects mice from obesity-related insulin resistance. Diabetes Obes Metab 3:360–366

    CAS  PubMed  CrossRef  Google Scholar 

  • Fain JN, Malbon CC (1979) Regulation of adenylate cyclase by adenosine. Mol Cell Biochem 25:143–169

    CAS  PubMed  CrossRef  Google Scholar 

  • Fain JN, Pointer RH, Ward WF (1972) Effects of adenosine nucleosides on adenylate cyclase, phosphodiesterase, cyclic adenosine monophosphate accumulation, and lipolysis in fat cells. J Biol Chem 247:6866–6872

    CAS  PubMed  Google Scholar 

  • Fatholahi M, Xiang Y, Wu Y, Li Y, Wu L, Dhalla AK, Belardinelli L, Shryock JC (2006) A novel partial agonist of the A1-adenosine receptor and evidence of receptor homogeneity in adipocytes. JPET 317:676–684

    CAS  CrossRef  Google Scholar 

  • Foley JE, Anderson RC, Bell PA, Burkey BF, Deems RO, de Souza C, Dunning BE (1997) Pharmacological strategies for reduction of lipid availability. Ann N Y Acad Sci 827:231–245

    CAS  PubMed  CrossRef  Google Scholar 

  • Fraser H, Gao Z, Ozeck MJ, Belardinelli L (2003) N-[3-(R)-Tetrahydrofuranyl]-6-aminopurine riboside, an A1 adenosine receptor agonist, antagonizes catecholamine-induced lipolysis without cardiovascular effects in awake rats. J Pharmacol Exp Ther 305:225–231

    CAS  PubMed  CrossRef  Google Scholar 

  • Fredholm BB, Sollevi A (1986) Cardiovascular effects of adenosine. Clin Physiol 6:1–21

    CAS  PubMed  CrossRef  Google Scholar 

  • Fredholm BB, IJzerman AP, Jacobson KA, Klotz KN, Linden J (2001) International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev 53:527–552

    CAS  Google Scholar 

  • Fruhbeck G, Gomez-Ambrosi J (2002) Depot-specific differences in the lipolytic effect of leptin on isolated white adipocytes. Med Sci Monit 8:BR47–BR55

    CAS  PubMed  Google Scholar 

  • Fruhbeck G, Gomez-Ambrosi J, Salvador J (2001) Leptin-induced lipolysis opposes the tonic inhibition of endogenous adenosine in white adipocytes. FASEB J 15:333–340

    CAS  PubMed  CrossRef  Google Scholar 

  • Funakoshi H, Zacharia LC, Tang Z, Zhang J, Lee LL, Good JC, Herrmann DE, Higuchi Y, Koch WJ, Jackson EK, Chan TO, Feldman AM (2007) A1 adenosine receptor upregulation accompanies decreasing myocardial adenosine levels in mice with left ventricular dysfunction. Circulation 115:2307–2315

    CAS  PubMed  CrossRef  Google Scholar 

  • Gao ZG, Jacobson KA (2007) Emerging adenosine receptor agonists. Expert Opin Emerg Drugs 12:479–492

    CAS  PubMed  CrossRef  Google Scholar 

  • Gao Z, Robeva AS, Linden J (1999) Purification of A1 adenosine receptor-G-protein complexes: effects of receptor down-regulation and phosphorylation on coupling. Biochem J 338 (Pt 3):729–736

    CAS  PubMed  CrossRef  Google Scholar 

  • Gardner CJ, Twissell DJ, Coates J, Strong P (1994) The effects of GR79236 on plasma fatty acid concentrations, heart rate and blood pressure in the conscious rat. Eur J Pharmacol 257:117–121

    CAS  PubMed  CrossRef  Google Scholar 

  • Garg A, Grundy SM (1990) Nicotinic acid as therapy for dyslipidemia in non-insulin-dependent diabetes mellitus. JAMA 264:723–726

    CAS  PubMed  CrossRef  Google Scholar 

  • Gines S, Ciruela F, Burgueno J, Casado V, Canela EI, Mallol J, Lluis C, Franco R (2001) Involvement of caveolin in ligand-induced recruitment and internalization of A(1) adenosine receptor and adenosine deaminase in an epithelial cell line. Mol Pharmacol 59:1314–1323

    CAS  PubMed  Google Scholar 

  • Gould J, Morton MJ, Sivaprasadarao A, Bowmer CJ, Yates MS (1997) Renal adenosine A1 receptor binding characteristics and mRNA levels during the development of acute renal failure in the rat. Br J Pharmacol 120:947–953

    CAS  PubMed  CrossRef  Google Scholar 

  • Grden M, Podgorska M, Szutowicz A, Pawelczyk T (2007) Diabetes-induced alterations of adenosine receptors expression level in rat liver. Exp Mol Pathol 83:392–398

    CAS  PubMed  CrossRef  Google Scholar 

  • Green A (1987) Adenosine receptor down-regulation and insulin resistance following prolonged incubation of adipocytes with an A1 adenosine receptor agonist. J Biol Chem 262:15702–15707

    CAS  PubMed  Google Scholar 

  • Green A, Swenson S, Johnson JL, Partin M (1989) Characterization of human adipocyte adenosine receptors. Biochem Biophys Res Commun 163:137–142

    CAS  PubMed  CrossRef  Google Scholar 

  • Green A, Johnson JL, Milligan G (1990) Down-regulation of Gi sub-types by prolonged incubation of adipocytes with an A1 adenosine receptor agonist. J Biol Chem 265:5206–5210

    CAS  PubMed  Google Scholar 

  • Grundy SM, Vega GL, McGovern ME, Tulloch BR, Kendall DM, Fitz-Patrick D, Ganda OP, Rosenson RS, Buse JB, Robertson DD, Sheehan JP, for the Diabetes Multicenter Research Group (2002) Efficacy, safety, and tolerability of once-daily niacin for the treatment of dyslipidemia associated with type 2 diabetes: results of the assessment of diabetes control and evaluation of the efficacy of Niaspan trial. Arch Intern Med 162:1568–1576

    CrossRef  Google Scholar 

  • Harada K, Shen WJ, Patel S, Natu V, Wang J, Osuga J, Ishibashi S, Kraemer FB (2003) Resistance to high-fat diet-induced obesity and altered expression of adipose-specific genes in HSL-deficient mice. Am J Physiol Endocrinol Metab 285: E1182–E1195

    CAS  PubMed  Google Scholar 

  • Ho RJ, Sutherland EW (1971) Formation and release of a hormone antagonist by rat adipocytes. J Biol Chem. 246:6822–6827

    CAS  PubMed  Google Scholar 

  • Hoffman BB, Chang H, Dall’Aglio E, Reaven GM (1986a) Desensitization of adenosine receptor-mediated inhibition of lipolysis. The mechanism involves the development of enhanced cyclic adenosine monophosphate accumulation in tolerant adipocytes. J Clin Invest 78:185–190

    CAS  Google Scholar 

  • Hoffman BB, Dall’Aglio E, Hollenbeck C, Chang H, Reaven GM (1986b) Suppression of free fatty acids and triglycerides in normal and hypertriglyceridemic rats by the adenosine receptor agonist phenylisopropyladenosine. JPET 239:715–718

    CAS  Google Scholar 

  • Ishikawa J, Mitani H, Bandoh T, Kimura M, Totsuka T, Hayashi S (1998) Hypoglycemic and hypotensive effects of 6-cyclohexyl-2-O-methyl-adenosine, an adenosine A1 receptor agonist, in spontaneously hypertensive rat complicated with hyperglycemia. Diabetes Res Clin Pract 39:3–9

    CAS  PubMed  CrossRef  Google Scholar 

  • Itani SI, Ruderman NB, Schmieder F, Boden G (2002) Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes 51:2005–2011

    CAS  PubMed  CrossRef  Google Scholar 

  • Jacobson KA, van Galen PJ, Williams M (1992) Adenosine receptors: pharmacology, structure–activity relationships, and therapeutic potential. J Med Chem 35:407–422

    CAS  PubMed  CrossRef  Google Scholar 

  • Jacobson KA, Von Lubitz DKJE, Daly JW, Fredholm BB (1996) Adenosine receptor ligands: differences with acute versus chronic treatment. TIPS 17:108–113

    CAS  PubMed  Google Scholar 

  • Jajoo S, Mukherjea D, Pingle S, Sekino Y, Ramkumar V (2006) Induction of adenosine A1 receptor expression by pertussis toxin via an adenosine 5-diphosphate ribosylation-independent pathway. JPET 317:1–10

    CAS  CrossRef  Google Scholar 

  • Jensen MD (2006) Adipose tissue as an endocrine organ: implications of its distribution on free fatty acid metabolism. Eur Heart J 8: B13–B19

    CAS  CrossRef  Google Scholar 

  • Johansson SM, Salehi A, Sandstrom ME, Westerblad H, Lundquist I, Carlsson PO, Fredholm BB, Katz A (2007a) A1 receptor deficiency causes increased insulin and glucagon secretion in mice. Biochem Pharmacol 74:1628–1635

    CAS  PubMed  CrossRef  Google Scholar 

  • Johansson SM, Yang JN, Lindgren E, Fredholm BB (2007b) Eliminating the antilipolytic adenosine A1 receptor does not lead to compensatory changes in the antilipolytic actions of PGE2 and nicotinic acid. Acta Physiol 190:87–96

    CAS  CrossRef  Google Scholar 

  • Kaartinen JM, Hreniuk SP, Martin LF, Ranta S, LaNoue KF, Ohisalo JJ (1991) Attenuated adenosine-sensitivity and decreased adenosine-receptor number in adipocyte plasma membranes in human obesity. Biochem J 279 (Pt 1):17–22

    CAS  PubMed  Google Scholar 

  • Kaartinen JM, LaNoue KF, Ohisalo JJ (1994) Quantitation of inhibitory G-proteins in fat cells of obese and normal-weight human subjects. Biochim Biophys Acta 1201:69–75

    CAS  PubMed  Google Scholar 

  • Kather H (1988) Purine accumulation in human fat cell suspensions. Evidence that human adipocytes release inosine and hypoxanthine rather than adenosine. J Biol Chem. 263:8803–8809

    CAS  Google Scholar 

  • Kenakin TP (1984) The classification of drugs and drug receptors in isolated tissues. Pharmacol Rev 36:165–222

    CAS  PubMed  Google Scholar 

  • Kenakin TP, Bond RA, Bonner TI (1992) Definition of pharmacological receptors. Pharmacol Rev 44:351–362

    CAS  PubMed  CrossRef  Google Scholar 

  • Klotz KN (2000) Adenosine receptors and their ligands. Naunyn–Schmiedeberg’s Arch Pharmacol 362:382–391

    CAS  CrossRef  Google Scholar 

  • Klotz K-N, Lohse MJ, Schwabe U, Cristalli G, Vittori S, Grifantini M (1989) 2-Chloro-N 6-[3H]cyclopentyladenosine ([3H]CCPA): a high 1 affinity agonist radioligand for A1 adenosine receptors. Naunyn–Schmiedeberg’s Arch Pharmacol 340:679–683

    CAS  CrossRef  Google Scholar 

  • Kollias-Baker C, Shryock JC, Belardinelli L (1995) Myocardial adenosine receptors. In: Belardinelli L, Pelleg A (eds) Adenosine and adenine nucleotides: from molecular biology to integrative physiology. Kluwer, Boston, pp 221–228

    Google Scholar 

  • Kollias-Baker CA, Ruble J, Jacobson M, Harrison JK, Ozeck M, Shryock JC, Belardinelli L (1997) Agonist-independent effect of an allosteric enhancer of the A1 adenosine receptor in CHO cells stably expressing the recombinant human A1 receptor. JPET 281:761–768

    CAS  Google Scholar 

  • Kovoor A, Celver JP, Wu A, Chavkin C (1998) Agonist induced homologous desensitization of mu-opioid receptors mediated by G protein-coupled receptor kinases is dependent on agonist efficacy. Mol Pharmacol 54:704–711

    CAS  PubMed  Google Scholar 

  • Lai DM, Tu YK, Liu IM, Cheng JT (2005) Increase of adenosine A1 receptor gene expression in cerebral ischemia of Wistar rats. Neurosci Lett 387:59–61

    CAS  PubMed  CrossRef  Google Scholar 

  • Langin D (2006) Adipose tissue lipolysis as a metabolic pathway to define pharmacological strategies against obesity and the metabolic syndrome. Pharmacol Res 53:482–491

    CAS  PubMed  CrossRef  Google Scholar 

  • LaNoue KF, Martin LF (1994) Abnormal A1 adenosine receptor function in genetic obesity. FASEB J 8:72–80

    CAS  PubMed  Google Scholar 

  • Large V, Arner P (1998) Regulation of lipolysis in humans. Pathophysiological modulation in obesity, diabetes, and hyperlipidaemia. Diabet Metab 24:409–418

    CAS  Google Scholar 

  • Larrouy D, Galitzky J, Lafontan M (1991) A1 adenosine receptors in the human fat cell: tissue distribution and regulation of radioligand binding. Eur J Pharmacol 206:139–147

    CAS  PubMed  CrossRef  Google Scholar 

  • Lasley RD, Narayan P, Uittenbogaard A, Smart EJ (2000) Activated cardiac adenosine A1 receptors translocate out of caveolae. J Biol Chem 275:4417–4421

    CAS  PubMed  CrossRef  Google Scholar 

  • Leblanc J, Soucy J (1994) Hormonal dose–response to an adenosine receptor agonist. Can J Physiol Pharmacol 72:113–116

    CAS  PubMed  Google Scholar 

  • Leung E, Jacobson KA, Green RD (1990) Analysis of agonist–antagonist interactions at A1 adenosine receptors. Mol Parmacol 38:72–83

    CAS  Google Scholar 

  • Liang HX, Belardinelli L, Ozeck MJ, Shryock JC (2002) Tonic activity of the rat adipocyte A1-adenosine receptor. Br J Pharmacol 135:1457–1466

    CAS  PubMed  CrossRef  Google Scholar 

  • Linden J (1991) Structure and function of A1 adenosine receptors. FASEB J 5:2668–2676

    CAS  PubMed  Google Scholar 

  • Liu IM, Tzeng TF, Tsai CC, Lai TY, Chang CT, Cheng JT (2003) Increase in adenosine A1 receptor gene expression in the liver of streptozotocin-induced diabetic rats. Diabet Metab Res Rev 19:209–215

    CAS  CrossRef  Google Scholar 

  • Lohse MJ, Ukena D, Schwabe U (1984) Adenosine receptors on heart muscle. Lancet 2:355

    CAS  Google Scholar 

  • Londos C, Wolff J (1977) Two distinct adenosine-sensitive sites on adenylate cyclase. Proc Natl Acad Sci USA 74:5482–5486

    CAS  PubMed  CrossRef  Google Scholar 

  • Longabaugh JP, Didsbury J, Spiegel A, Stiles GL (1989) Modification of the rat adipocyte A1 adenosine receptor-adenylate cyclase system during chronic exposure to an A1 adenosine receptor agonist: alterations in the quantity of Gs alpha and Gi alpha are not associated with changes in their mRNAs. Mol Pharmacol 36:681–688

    CAS  PubMed  Google Scholar 

  • Lorenzen A, Sebastiao AM, Sellink A, Vogt H, Schwabe U, Ribeiro JA, IJzerman AP (1997) Biological activities of N 6, C8-disubstituted adenosine derivatives as partial agonists at rat brain adenosine A1 receptors. Eur J Pharmacol 334:299–307

    CAS  PubMed  CrossRef  Google Scholar 

  • Mathot RAA, van der Wenden EM, Soudijn W, IJzerman AP, Danhof M (1995) Deoxyribose analogues of N 6-cyclopentyladenosine (CPA): partial agonists at the adenosine A1 receptor in vivo. Br J Pharmacol 116:1957–1964

    CAS  PubMed  Google Scholar 

  • McKenny JM, Proctor JD, Harris S, Chinchili VM (1994) A comparison of the efficacy and toxic effects of sustained vs immediate-release niacin in hypercholesterolemic patients. JAMA 271:672–710

    CrossRef  Google Scholar 

  • Merkel LA, Hawkins ED, Colussi DJ, Greenland BD, Smits GJ, Perrone MH, Cox BF (1995) Cardiovascular and antilipolytic effects of the adenosine agonist GR79236. Pharmacology 51:224–236

    CAS  PubMed  CrossRef  Google Scholar 

  • Meyer P, Bier D, Holschbach M, Cremer M, Tellmann L, Bauer A (2003) In vivo imaging of rat brain A1 adenosine receptor occupancy by caffeine. Eur J Nucl Med Mol Imag 30:1440

    CrossRef  Google Scholar 

  • Moreno FJ, Mills I, Garcia-Sainz JA, Fain JN (1983) Effects of pertussis toxin treatment on the metabolism of rat adipocytes. J Biol Chem 258(18):10938–10943

    CAS  PubMed  Google Scholar 

  • Morey TE, Belardinelli L, Dennis DM (1998) Validation of Furchgott’s method to determine agonist-dependent A1-adenosine receptor reserve in guinea-pig atrium. Br J Pharmacol 123:1425–1433

    CAS  PubMed  CrossRef  Google Scholar 

  • Morrison CF, Elzein E, Jiang B, Ibrahim PN, Marquart T, Palle V, Shenk KD, Varkhedkar V, Maa T, Wu L, Wu Y, Zeng D, Fong I, Lustig D, Leung K, Zablocki JA (2004) Structure–affinity relationships of 5-aromatic ethers and 5-aromatic sulfides as partial A1 adenosine agonists, potential supraventricular anti-arrhythmic agents. Bioorg Med Chem Lett 14:3793–3797

    CAS  PubMed  CrossRef  Google Scholar 

  • Muller CE (2001) A1 adenosine receptors and their ligands: overview and recent developments. Il Farmaco 56:77–80

    CAS  PubMed  CrossRef  Google Scholar 

  • Munshi R, Pang IH, Sternweis PC, Linden J (1991) A1 adenosine receptors of bovine brain couple to guanine nucleotide-binding proteins Gi1, Gi2, and Go. J Biol Chem 266:22285–22289

    CAS  PubMed  Google Scholar 

  • Murray TF (1982) Up-regulation of rat cortical adenosine receptors following chronic administration of theophylline. Eur J Pharmacol 82:113–114

    CAS  PubMed  CrossRef  Google Scholar 

  • Nemeth ZH, Bleich D, Csoka B, Pacher P, Mabley JG, Himer L, Vizi ES, Deitch EA, Szabo C, Cronstein BN, Hasko G (2007) Adenosine receptor activation ameliorates type 1 diabetes. FASEB J 21:2379–2388

    CAS  PubMed  CrossRef  Google Scholar 

  • Nie Z, Mei Y, Ford M, Rybak L, Marcuzzi A, Ren H, Stiles GL, Ramkumar V (1998) Oxidative stress increases A1 adenosine receptor expression by activating nuclear factor kappa B. Mol Pharmacol 53:663–669

    CAS  PubMed  Google Scholar 

  • Okajima F, Sato K, Sho K, Kondo Y (1989) Stimulation of adenosine receptor enhances A1-adrenergic receptor-mediated activation of phospholipase C and Ca2 + mobilization in a pertussis toxin-sensitive manner in FRTL-5 thyroid cells. FEBS Lett 248:145–149

    CAS  PubMed  CrossRef  Google Scholar 

  • Osuga J, Ishibashi S, Oka T, Yagyu H, Tozawa R, Fujimoto A, Shionoiri F, Yahagi N, Kraemer FB, Tsutsumi O, Yamada N (2000) Targeted disruption of hormone-sensitive lipase results in male sterility and adipocyte hypertrophy, but not in obesity. Proc Natl Acad Sci USA 97:787–792

    CAS  PubMed  CrossRef  Google Scholar 

  • Palle VP, Varkhedkar V, Ibrahim P, Ahmed H, Li Z, Gao Z, Ozeck M, Wu Y, Zeng D, Wu L, Leung K, Chu N, Zablocki JA (2004) Affinity and intrinsic efficacy (IE) of 5-carbamoyl adenosine analogues for the A1 adenosine receptor–efforts towards the discovery of a chronic ventricular rate control agent for the treatment of atrial fibrillation (AF). Bioorg Med Chem Lett 14:535–539

    CAS  PubMed  CrossRef  Google Scholar 

  • Palmer TM, Benovic JL, Stiles GL (1996) Molecular basis for subtype-specific desensitization of inhibitory adenosine receptors. Analysis of a chimeric A1 − A3 adenosine receptor. J Biol Chem 271:15272–15278

    CAS  PubMed  CrossRef  Google Scholar 

  • Parsons WJ, Stiles GL (1987) Heterologous desensitization of the inhibitory A1 adenosine receptor–adenylate cyclase system in rat adipocytes. Regulation of both Ns and Ni. J Biol Chem 262:841–847

    CAS  Google Scholar 

  • Pawelczyk T, Grden M, Rzepko R, Sakowicz M, Szutowicz A (2005) Region-specific alterations of adenosine receptors expression level in kidney of diabetic rat. Am J Pathol 167:315–325

    CAS  PubMed  Google Scholar 

  • Poulsen S, Quinn RJ (1998) Adenosine receptors: new opportunities for future drugs. Bioorg Med Chem 6:619–641

    CAS  PubMed  CrossRef  Google Scholar 

  • Poynten AM, Gan SK, Kriketos AD, O’Sullivan A, Kelly JJ, Ellis BA, Chisholm DJ, Campbell LV (2003) Nicotinic acid-induced insulin resistance is related to increased circulating fatty acids and fat oxidation but not muscle lipid content. Metabolism 52:699–704

    CAS  PubMed  CrossRef  Google Scholar 

  • Press NJ, Gessi S, Borea PA, Polosa R (2007) Therapeutic potential of adenosine receptor antagonists and agonists. Expert Opin Ther Patents 17:979–991

    CAS  CrossRef  Google Scholar 

  • Qu X, Cooney G, Donnelly R (1997) Short-term metabolic and haemodynamic effects of GR79236 in normal and fructose-fed rats. Eur J Pharmacol 338:269–276

    CAS  PubMed  CrossRef  Google Scholar 

  • Ramkumar V, Bumgarner JR, Jacobson KA, Stiles GL (1988) Multiple components of the A1 adenosine receptor–adenylate cyclase system are regulated in rat cerebral cortex by chronic caffeine ingestion. J Clin Invest 82:242–247

    CAS  PubMed  CrossRef  Google Scholar 

  • Reaven GM (1995) The fourth musketeer: from Alexandre Dumas to Claude Bernard. Diabetologia 38:3–13

    CAS  PubMed  CrossRef  Google Scholar 

  • Reaven GM, Chang H, Ho H, Jeng CY, Hoffman BB (1988) Lowering of plasma glucose in diabetic rats by antilipolytic agents. Am J Physiol 254:E23–E30

    CAS  PubMed  Google Scholar 

  • Reppert SM, Weaver DR, Stehle JH, Rivkees SA (1991) Molecular cloning and characterization of a rat A1-adenosine receptor that is widely expressed in brain and spinal cord. Mol Endocrin 5:1037–1048

    CAS  CrossRef  Google Scholar 

  • Rivkees SA (1995) The ontogeny of cardiac and neural A1 adenosine receptor expression in rats. Dev Brain Res 89:202–213

    CAS  CrossRef  Google Scholar 

  • Roden M, Price TB, Perseghin G, Petersen KF, Rothman DL, Cline GW, Shulman GI (1996) Mechanism of free fatty acid-induced insulin resistance in humans. J Clin Invest 97:2859–2865

    CAS  PubMed  CrossRef  Google Scholar 

  • Rogachev B, Ziv NY, Mazar J, Nakav S, Chaimovitz C, Zlotnik M, Douvdevani A (2006) Adenosine is upregulated during peritonitis and is involved in downregulation of inflammation. Kidney Int 70:675–681

    CAS  PubMed  CrossRef  Google Scholar 

  • Rolband GC, Furth ED, Staddon JM, Rogus EM, Goldberg AP (1990) Effects of age and adenosine in the modulation of insulin action on rat adipocyte metabolism. J Gerontol 45:B174–B178

    Google Scholar 

  • Ruffolo RR (1982) Important concepts of receptor theory. J Auton Pharmacol 2:277–295

    CAS  PubMed  CrossRef  Google Scholar 

  • Saggerson ED, Jamal Z (1990) Differences in the properties of A1-type adenosine receptors in rat white and brown adipocytes. Biochem J 269:157–161

    CAS  PubMed  Google Scholar 

  • Sako Y, Grill VE (1990) A 48-h lipid infusion in the rat time-dependently inhibits glucose-induced insulin secretion and B cell oxidation through a process likely coupled to fatty acid oxidation. Endocrinology 127:1580–1589

    CAS  PubMed  CrossRef  Google Scholar 

  • Schiffmann SN, Libert F, Vassart G, Dumont JE, Vanderhaeghen JJ (1990) A cloned G protein-coupled protein with a distribution restricted to striatal medium-sized neurons. Possible relationship with D1 dopamine receptor. Brain Res 519:333–337

    CAS  PubMed  CrossRef  Google Scholar 

  • Schoelch C, Kuhlmann J, Gossel M, Mueller G, Neumann-Haefelin C, Belz U, Kalisch J, Biemer-Daub G, Kramer W, Juretschke HP, Herling AW (2004) Characterization of adenosine-A1 receptor-mediated antilipolysis in rats by tissue microdialysis, 1H-spectroscopy, and glucose clamp studies. Diabetes 53:1920–1926

    CAS  PubMed  CrossRef  Google Scholar 

  • Schrader J, Baumann G, Gerlach E (1977) Adenosine as inhibitor of myocardial effects of catecholamines. Pflugers Arch 372:29–35

    CAS  PubMed  CrossRef  Google Scholar 

  • Schwabe U, Ebert R (1974) Stimulation of cyclic adenosine 3, 5-monophosphate accumulation and lipolysis in fat cells by adenosine deaminase. Naunyn–Schmiedeberg’s Arch Pharmacol 282:33–44

    CAS  CrossRef  Google Scholar 

  • Schwabe U, Ebert R, Erbler C (1973) Adenosine release from isolated fat cells and its significance for the effects of hormones on cyclic 3, 5-AMP levels and lipolysis. Naunyn–Schmiedeberg’s Arch Pharmacol 276:133–148

    CAS  CrossRef  Google Scholar 

  • Schwabe U, Schonhofer PS, Ebert R (1974) Facilitation by adenosine of the action of insulin on the accumulation of adenosine 3, 5-monophosphate, lipolysis, and glucose oxidation in isolated fat cells. Eur J Biochem 46:537–545

    CAS  PubMed  CrossRef  Google Scholar 

  • Shah B, Rohatagi S, Natarajan C, Kirkesseli S, Baybutt R, Jensen BK (2004) Pharmacokinetics, pharmacodynamics, and safety of a lipid-lowering adenosine A1 agonist, RPR749, in healthy subjects. Am J Ther 11:175–189

    PubMed  CrossRef  Google Scholar 

  • Shen J, Halenda SP, Sturek M, Wilden P (2005) Novel mitogenic effect of adenosine on coronary artery smooth muscle cells. Circ Res 96:982–990

    CAS  PubMed  CrossRef  Google Scholar 

  • Srinivas M, Shryock JC, Dennis DM, Baker SP, Belardinelli L (1997) Differential A1 adenosine receptor reserve for two actions of adenosine on guinea pig atrial myocytes. Mol Pharmacol 52:683–691

    CAS  PubMed  Google Scholar 

  • Stephenson RP (1997) A modification of receptor theory. 1956. Br J Pharmacol 120:106–120

    CAS  PubMed  Google Scholar 

  • Strange PG (2008) Agonist binding, agonist affinity and agonist efficacy at G protein-coupled receptors. Br J Pharmacol 153:1353–1363

    CAS  PubMed  CrossRef  Google Scholar 

  • Strong P, Anderson R, Coates J, Ellis F, Evans B, Gurden MF, Johnstone J, Kennedy I, Martin DP (1993) Suppression of non-esterified fatty acids and triacylglycerol in experimental animals by the adenosine analogue GR79236. Clin Sci 84:663–669

    CAS  PubMed  Google Scholar 

  • Szot P, Sanders RC, Murray TF (1987) Theophylline-induced upregulation of A1-adenosine receptors associated with reduced sensitivity to convulsants. Neuropharmacology 26:1173–1180

    CAS  PubMed  CrossRef  Google Scholar 

  • Takasuga S, Katada T, Ui M, Hazeki O (1999) Enhancement by adenosine of insulin-induced activation of phosphoinositide 3-kinase and protein kinase B in rat adipocytes. J Biol Chem 274:19545–19550

    CAS  PubMed  CrossRef  Google Scholar 

  • Tatsis-Kotsidis I, Erlanger BF (1999) Initiation of a process of differentiation by stable transfection of ob17 preadipocytes with the cDNA of human A1 adenosine receptor. Biochem Pharmacol 58:167–170

    CAS  PubMed  CrossRef  Google Scholar 

  • Thompson CS, Strong P, Mikhailidis DP (1994) Interactions between insulin and the antilipolytic agent GR79236 in ketoacidotic diabetic rats. J Drug Dev 6:183–186

    CAS  Google Scholar 

  • Trost T, Schwabe U (1981) Adenosine receptors in fat cells. Identification by ( − )-N 6-[3H]phenylisopropyladenosine binding. Mol Pharmacol 19:228–235

    CAS  PubMed  Google Scholar 

  • Ukena D, Furler R, Lohse MJ, Engel G, Schwabe U (1984a) Labelling of Ri adenosine receptors in rat fat cell membranes with ( − )-[125iodo]N 6-hydroxyphenylisopropyladenosine. Naunyn–Schmiedeberg’s Arch Pharmacol 326:233–240

    CAS  CrossRef  Google Scholar 

  • Ukena D, Poeschla E, Schwabe U (1984b) Guanine nucleotide and cation regulation of radioligand binding to Ri adenosine receptors of rat fat cells. Naunyn–Schmiedeberg’s Arch Pharmacol 326:241–247

    CAS  CrossRef  Google Scholar 

  • Vachon L, Costa T, Herz A (1987) Opioid receptor desensitization in NG 108–15 cells. Differential effects of a full and a partial agonist on the opioid-dependent GTPase. Biochem Pharmacol 36:2889–2897

    CAS  Google Scholar 

  • Van der Graaf PH, van Schaick EA, Visser SAG, De Greef HJMM, IJzerman AP, Danhof M (1999) Mechanism-based pharmacokinetic–pharmacodynamic modeling of antilipolytic effects of adenosine A1 receptor agonists in rats: prediction of tissue-dependent efficacy in vivo. J Pharmacol Exp Ther 290:702–709

    PubMed  Google Scholar 

  • van der Wenden EM, von Frijtag Drabbe Kunzel JK, Mathot RA, Danhof M, IJzerman AP, Soudijn W (1995) Ribose-modified adenosine analogues as potential partial agonists for the adenosine receptor. J Med Chem 38:4000–4006

    PubMed  CrossRef  Google Scholar 

  • van Schaick EA, Tukker HE, Roelen HCPF, IJzerman AP, Danhof M (1998a) Selectivity of action of 8-alkylamino analogues of N 6-cyclopentyladenosine in vivo: haemodynamic versus anti-lipolytic responses in rats. Br J Pharmacol 124:607–618

    PubMed  CrossRef  Google Scholar 

  • van Schaick EA, Zuideveld KP, Tukker HE, Langemeijer MW, IJzerman AP, Danhof M (1998b) Metabolic and cardiovascular effects of the adenosine A1 receptor agonist N 6-(p-sulfophenyl)adenosine in diabetic Zucker rats: influence of the disease on the selectivity of action. JPET 287:21–30

    Google Scholar 

  • van Tilburg EW, van der Klein PA, Frijtag Drabbe KJ, de Groote M, Stannek C, Lorenzen A, IJzerman AP (2001) 5-O-Alkyl ethers of N,2-substituted adenosine derivatives: partial agonists for the adenosine A1 and A3 receptors. J Med Chem 44:2966–2975

    PubMed  CrossRef  CAS  Google Scholar 

  • Vannucci SJ, Klim CM, Martin LF, LaNoue KF (1989) A1-adenosine receptor-mediated inhibition of adipocyte adenylate cyclase and lipolysis in Zucker rats. Am J Physiol 257: E871-E878

    CAS  PubMed  Google Scholar 

  • Vassaux G, Gaillard D, Mari B, Ailhaud G, Negrel R (1993) Differential expression of adenosine A1 and A2 receptors in preadipocytes and adipocytes. Biochem Biophys Res Commun 193:1123–1130

    CAS  PubMed  CrossRef  Google Scholar 

  • Vega GL, Cater NB, Meguro S, Grundy SM (2005) Influence of extended-release nicotinic acid on nonesterified fatty acid flux in the metabolic syndrome with atherogenic dyslipidemia. Am J Cardiol 95:1309–1313

    CAS  PubMed  CrossRef  Google Scholar 

  • Wagner H, Milavec-Krizman M, Gadient F, Menninger K, Schoeffter P, Tapparelli C, Pfannkuche H-J, Fozard JR (1995) General pharmacology of SDZ WAG 994, a potent selective and orally active adenosine A1 receptor agonist. Drug Dev Res 34:276–288

    CAS  CrossRef  Google Scholar 

  • Wu SN, Linden J, Visentin S, Boykin M, Belardinelli L (1989) Enhanced sensitivity of heart cells to adenosine and up-regulation of receptor number after treatment of guinea pigs with theophylline. Circ Res 65:1066–1077

    CAS  PubMed  Google Scholar 

  • Wu L, Belardinelli L, Zablocki JA, Palle V, Shryock JC (2001) A partial agonist of the A(1)-adenosine receptor selectively slows AV conduction in guinea pig hearts. Am J Physiol Heart Circ Physiol 280:H334–H343

    CAS  PubMed  Google Scholar 

  • Wyne KL (2003) Free fatty acids and type 2 diabetes mellitus. Am J Med 115(Suppl 8A):29S–36S

    CAS  PubMed  CrossRef  Google Scholar 

  • Xu B, Berkich DA, Crist GH, LaNoue KF (1998) A1 adenosine receptor antagonism improves glucose tolerance in Zucker rats. Am J Physiol 274:E271–E279

    CAS  PubMed  Google Scholar 

  • Zannikos PN, Rohatagi S, Jensen BK (2001) Pharmacokinetic–pharmacodynamic modeling of the antilipolytic effects of an adenosine receptor agonist in healthy volunteers. J Clin Pharmacol 41:61–69

    CAS  PubMed  CrossRef  Google Scholar 

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Dhalla, A.K., Chisholm, J.W., Reaven, G.M., Belardinelli, L. (2009). A1 Adenosine Receptor: Role in Diabetes and Obesity. In: Wilson, C., Mustafa, S. (eds) Adenosine Receptors in Health and Disease. Handbook of Experimental Pharmacology, vol 193. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-89615-9_9

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