Desensitization of adenosine receptor-mediated inhibition of lipolysis. The mechanism involves the development of enhanced cyclic adenosine monophosphate accumulation in tolerant adipocytes.

Abstract

Adipocytes contain adenosine receptors, termed Al receptors, which inhibit lipolysis by decreasing adenylate cyclase activity. The inhibition of lipolysis by adenosine agonists in vivo acutely suppresses the plasma concentrations of free fatty acids (FFA) and triglycerides. We have found that infusions of the adenosine receptor agonist phenylisopropyladenosine (PIA) initially decreases plasma FFA concentrations; however, with prolonged exposure (6 d), rats become very tolerant to the effects of the drug. Adipocytes isolated from epididymal fat pads from PIAinfused rats have altered lipolytic responses. When lipolysis is stimulated with a relatively high concentration of isoproterenol (10-' M), PIA does not inhibit lipolysis in adipocytes from the infused animals. However, PIA inhibits isoproterenol-stimulated cyclic AMP (cAMP) accumulation in adipocytes from the infused rats although with decreased sensitivity compared with controls. The explanation for the impaired antilipolytic effect appears to be due to the fact that isoproterenol-stimulated cAMP accumulation is markedly increased in cells from infused rats. Indeed, basal lipolysis and lipolysis stimulated with lower concentrations of isoproterenol (10-9, 10-8 M) are effectively inhibited by PIA. cAMP accumulation is greatly increased in adipocytes from infused rats when stimulated by isoproterenol, ACTH, and forskolin. The results have some striking analogies to changes induced in nerve cells by prolonged exposure to narcotics. These data suggest that tolerance to PIA develops in adipocytes as a consequence of enhanced cAMP accumulation.

Sequential Synthesis and Methylation of Phosphatidylethanolamine Promote Lipid Droplet Biosynthesis and Stability in Tissue Culture and in Vivo

“…Previous results suggested that adenosine-receptor agonists (such as PIA) effectively reduce the levels of both plasma triglycerides and unesterified fatty acids when infused into rats (63). Our results emphasize that 3T3-L1 adipocytes with a down-regulated PEMT gene exhibit considerably increased basal lipolysis, and fat pads from Pemt Ϫ/Ϫ mice show a moderate increase in basal lipolysis in comparison with those of WT animals.…”

“…Adipocytes express adenosine A1 receptors (62) that effectively suppress adenylate cyclase, thereby inhibiting catecholamine-mediated triglyceride hydrolysis (63). Previous results suggested that adenosine-receptor agonists (such as PIA) effectively reduce the levels of both plasma triglycerides and unesterified fatty acids when infused into rats (63).…”

A1adenosine receptor partial agonist lowers plasma FFA and improves insulin resistance induced by high-fat diet in rodents

“…Consequently, it is possible to achieve a greater functional selectivity using partial agonists than full agonists; e.g., CVT-3619 does not significantly affect heart rate and blood pressure at doses that have significant antilipolytic activity (8). Furthermore, partial agonists of G protein-coupled receptors have been suggested to cause less pronounced receptor desensitization (19,37) than full agonists with prolonged and continuous exposure (16,23). In that context, we have shown that the antilipolytic effects (the magnitude and the duration the FFA-lowering effect) of CVT-3619 are well-maintained over three consecutive acute administrations (8); however, it remains to be determined whether the antilipolytic effect of CVT-3619 is sustained over long-term use.…”

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

“…The magnitude and the duration of the FFA-lowering effect of CVT-3619 were similar for all three injections, suggesting that the effect of this agonist does not undergo tachyphylaxis. Desensitization of the antilipolytic effect of A 1 receptors has been shown to occur with prolonged and continuous exposure to high concentrations of an A 1 agonist, R-PIA (Hoffman et al, 1986a). R-PIA is a full agonist and thus more likely to cause desensitization.…”