Attenuated adenosine-sensitivity and decreased adenosine-receptor number in adipocyte plasma membranes in human obesity

Abstract

Fat-cells were isolated from patients of body-mass indices (BMIs) ranging from 17.9 to 83.9 kg/m2. Isoprenaline-stimulated cyclic AMP accumulation in cells prepared from obese subjects as compared with normal-weight subjects, was less sensitive to inhibition by the adenosine agonist N6-(phenylisopropyl)adenosine (PIA) (P = 0.047). The inhibition of 7 beta-desacetyl-7 beta-[gamma-(N-methylpiperazino) butyryl]-forskolin-stimulated adenylate cyclase by PIA in the presence of adenosine deaminase was also much attenuated in crude plasma membranes of adipocytes prepared from massively obese patients as compared with lean controls (P = 0.0143). This difference was probably not due to different cell size, because adenylate cyclase of crude plasma membranes of large adipocytes was actually more sensitive to PIA than was adenylate cyclase of membranes of smaller fat-cells co-isolated from the same individual. The stimulatory effect of PIA on glucose uptake in the presence of adenosine deaminase was depressed in adipocytes prepared from obese subjects and correlated with BMI at r = -0.626 (P = 0.007) at 100 nM-PIA. The adenosine receptors were studied by using the adenosine antagonist 1,3-[3H]dipropyl-8-cyclopentylxanthine. The binding was rapid and proportional to protein concentration. There was no difference in the affinities of receptors in membranes of obese and normal-weight subjects; Kd values of all patients averaged 3.3 nM. Bmax values were 54 and 130 fmol/mg of protein in membranes prepared from seven obese and five control patients respectively. The Bmax values calculated per mg of protein correlated with BMI at r = -0.539 (P = 0.047). The adenosine content of adipose tissue was higher in obese than in control subjects. These results demonstrate an attenuated response of cyclic AMP accumulation, adenylate cyclase and glucose uptake to adenosine in fat-cells prepared from obese subjects, and suggest that this change is at least partly due to changes in the amount of adenosine receptors, but not their affinity. The decreased receptor number could be due to higher adenosine content. A higher adenosine concentration in adipose tissue could explain why lipolysis is inhibited in situ in obesity, and the desensitization could explain the diminished response to adenosine analogues in isolated fat-cells.

Activation of the A1adenosine receptor increases insulin-stimulated glucose transport in isolated rat soleus muscle

“…The effects are predominantly at the level of skeletal muscle . Moreover, abnormal adenosine receptor function has been reported in obesity and diabetes (LaNoue and Martin 1994; Kaartinen et al 1991;Green and Johnson 1991) and might functionally contribute to the development of insulin resistance that characterizes these diseases. These findings lead us to speculate that if one were to develop a safe agent that would activate these receptors, it would be beneficial to those with insulin resistance.…”

“…Adenosine regulates an array of key physiological processes in virtually every cell and organ system (Newby et al 1985;Linden 2001; and has been proposed to provide a protective mechanism against injurious stimuli (Newby et al 1990;Linden 2001). Furthermore, alterations in adenosine receptor numbers and functions in obese humans (Kaartinen et al 1991) and impaired coupling of adenosine receptors to G-proteins in genetic models of obesity (LaNoue and Martin 1994) and diabetes (Green and Johnson 1991) have been reported.…”

Low Coronary Microcirculatory Resistance Associated With Profound Hypotension During Intravenous Adenosine Infusion

“…A 1 receptor agonists are less potent in obese animals, and the concentration of A 1 receptors is lower in adipocytes isolated from obese humans compared with nonobese. 37,38,39 Furthermore, the decrease in these receptors, which is attributed to downregulation, is negatively correlated with body mass index. 38 Although the translation of these findings from the adipose to the vascular tissue is speculative, proportional changes in subtypes of adenosine receptors among different human tissues have been observed, 40 providing biological plausibility to this hypothesis.…”

“…37,38,39 Furthermore, the decrease in these receptors, which is attributed to downregulation, is negatively correlated with body mass index. 38 Although the translation of these findings from the adipose to the vascular tissue is speculative, proportional changes in subtypes of adenosine receptors among different human tissues have been observed, 40 providing biological plausibility to this hypothesis. Taken all together, our observation is supported by available information that suggests that obesity might be related to profound hypotensive responses to intravenous adenosine either through an impaired sympathetic autonomic or possibly through an impaired adenosine A 1 receptor function.…”

Hormone sensitive lipase expression and adipose tissue metabolism show gender difference in obese subjects after weight loss

“…The subjects were, however, still obese after 1 y weight loss, which may explain the unexpectedly low maximal stimulation of lipolysis. Obesity can cause attenuated responses in adipose tissue due to desensitization 28,52 or enhanced basal lipolysis so that responses to stimulation or inhibition before and after weight loss might be weaker than expected.…”