Characterization of Adenosine-A1 Receptor–Mediated Antilipolysis in Rats by Tissue Microdialysis, 1H-Spectroscopy, and Glucose Clamp Studies

Abstract

Increased supply of fatty acids to muscle and liver is causally involved in the insulin resistance syndrome. Using a tissue microdialysis technique in Wistar and Zucker fatty (ZF) rats, we determined tissue glycerol levels as a marker of lipolysis in gastrocnemius muscle (gMT), subcutaneous adipose (SAT), and visceral adipose tissue (VAT) as well as the reduction of plasma free fatty acids, glycerol, and triglycerides caused by the antilipolysis-specific adenosine-A1 receptor agonist (ARA). In Wistar and ZF rats, ARA significantly lowered dialysate glycerol levels in SAT, VAT, and gMT. Whereas in SAT and VAT the decrease in dialysate glycerol indicated adipocytic antilipolysis, this decrease in gMT was not caused by a direct effect of ARA on intramyocellular lipolysis, as demonstrated by the lack of inhibition of the protein kinase A activity ratio in gMT. In addition, no differences of the fed-starved-refed dynamics of intramyocellular triglyceride levels compared with untreated controls were measured by in vivo 1 Hspectroscopy, excluding any adenylate cyclase-independent antilipolysis in muscle. Treatment with ARA resulted in pronounced reductions of plasma free fatty acids, glycerol, and triglycerides. Furthermore, in ZF rats, ARA treatment caused an immediate improvement of peripheral insulin sensitivity measured by the euglycemic-hyperinsulinemic glucose clamp technique.

Antilipolytic Activity of a Novel Partial A1Adenosine Receptor Agonist Devoid of Cardiovascular Effects: Comparison with Nicotinic Acid

“…These data are consistent with previous reports showing that other A 1 agonists decrease FFA levels (Hoffman et al, 1986b;Gardner et al, 1994;Fraser et al, 2003;Schoelch et al, 2004). The FFA-lowering effect of CVT-3619 was completely antagonized by pretreatment with an A 1 antagonist, DPCPX, confirming that these effects are mediated via A 1 receptors.…”

“…The antilipolytic actions of adenosine that are mediated by A 1 receptors have been known for many years (Hoffman et al, 1986b;Gardner et al, 1994;Fraser et al, 2003;Schoelch et al, 2004). The metabolic responses after acute administration of many A 1 agonists have been reported previously; however, no compound has been developed and approved for clinical use thus far.…”

“…A 1 adenosine receptor agonists are well recognized antilipolytic agents due to their effect of reducing the formation and release of FFA from adipose tissue (Hoffman et al, 1986b;Gardner et al, 1994;Dhalla et al, 2003;Fraser et al, 2003;Schoelch et al, 2004;Fatholahi et al, 2006). A 1 agonists reduce lipolysis [breakdown of triglyceride (TG) to FFA] in adipose tissue by inhibiting adenylyl cyclase activity and cAMP formation (Fain et al, 1972;Schwabe et al, 1974).…”

Contrasting effects of A1 and A2b adenosine receptors on adipogenesis

“…9 The A1R also has a physiological role in protecting against obesity-related insulin resistance, 10 and agonism of the A1R has been shown to lower plasma-free fatty acids and glycerol in obese Zucker fatty animals. 7 Glucose-stimulated insulin and glucagon secretion were also elevated in A1R null mice when compared with wild-type animals. 11 In addition, consumption of large quantities of caffeine has been reported to be beneficial and associated with a reduced risk of type 2 diabetes, 12 however, the mechanisms involved remain unclear.…”

“…3,4 Adenosine, acting through A1R, has been implicated in many of the physiological functions of adipocytes. It has been associated, in particular, with an inhibition of lipolysis [5][6][7] and can be considered as a possible target for inclusion in the overall management of obesity. Furthermore, it is known that A1R activation mediates leptin secretion in animal models, 8 and blocking of the receptor or removal of endogenous adenosine reduces leptin secretion from isolated adipocytes.…”