Adenosine Receptors in Health and Disease

Volume 193 of the series Handbook of Experimental Pharmacology pp 271-295


A1 Adenosine Receptor: Role in Diabetes and Obesity

  • Arvinder K. DhallaAffiliated withDepartment of Pharmacological Sciences, CV Therapeutics Inc. Email author 
  • , Jeffrey W. ChisholmAffiliated withDepartment of Pharmacological Sciences, CV Therapeutics
  • , Gerald M. ReavenAffiliated withDivision of Cardiovascular Medicine, Stanford University School of Medicine
  • , Luiz BelardinelliAffiliated withDepartment of Pharmacological Sciences, CV Therapeutics

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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.


A1 Adenosine Receptor Antilipolytic Insulin Resistance Diabetes Obesity