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A1 Adenosine Receptor: Role in Diabetes and Obesity

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Adenosine Receptors in Health and Disease

Part of the book series: Handbook of Experimental Pharmacology ((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.

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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

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Authors and Affiliations

  1. Department of Pharmacological Sciences, CV Therapeutics Inc., 3172 Porter Drive, Palo Alto, CA, 94304, USA

    Arvinder K. Dhalla

  2. Department of Pharmacological Sciences, CV Therapeutics, 3172 Porter Drive, Palo Alto, CA, 94304, USA

    Jeffrey W. Chisholm

  3. Division of Cardiovascular Medicine, Stanford University School of Medicine, 300 Pasteur Dr. CVRC MC: 5406, Stanford, CA, 94305, USA

    Gerald M. Reaven

  4. Department of Pharmacological Sciences, CV Therapeutics, 3172 Porter Drive, Palo Alto, CA, 94304, USA

    Luiz Belardinelli

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  1. Arvinder K. Dhalla
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  2. Jeffrey W. Chisholm
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  3. Gerald M. Reaven
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  4. Luiz Belardinelli
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Correspondence to Arvinder K. Dhalla .

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  1. Endacea, Inc.,, Davis Drive 2, Research Triangle Park, 27709-2076, U.S.A.

    Constance N. Wilson

  2. Health Sciences Center, West Virginia University, Health Sciences S. 2267, Morgantown, 26506-9104, U.S.A.

    S. Jamal Mustafa

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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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