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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-2109
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 5 1882-1886
Copyright © 2006 by The Endocrine Society

Differences in the Expression of the Adenosine A1 Receptor in Adipose Tissue of Obese Black and White Women

Hisham Barakat, Julianne Davis, David Lang, S. Jamal Mustafa and Mona M. McConnaughey

Departments of Medicine (H.B., J.D., D.L.) and Pharmacology (M.M.M.), Brody School of Medicine, East Carolina University, Greenville, North Carolina 27858; and Department of Physiology and Pharmacology (S.J.M.), School of Medicine, West Virginia University, Morgantown, West Virginia 26505

Address all correspondence and requests for reprints to: Hisham Barakat, Ph.D., Department of Medicine, Brody School of Medicine, East Carolina University, Greenville, North Carolina 27858. E-mail: Barakath{at}ecu.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: African-American women (AAW) lose less weight and at a slower rate than Caucasian women (CAW) under the same weight-loss regimens. A potential cause of this finding is inhibition of lipolysis.

Objective: Because {alpha}-2 and adenosine receptors are directly involved in inhibition of lipolysis, differences in {alpha}-2 or adenosine A1 receptors in visceral adipose tissue (VAT) and sc adipose tissue (SAT) from obese AAW and CAW were determined.

Design: Measurements of maximal binding capacity (Bmax) of {alpha}-2 and adenosine A1 receptors as well as protein and mRNA levels of the adenosine receptor in VAT and SAT from AAW and CAW were taken.

Setting: The study was conducted in the general community.

Patients: Patients were selected by body mass index greater than 40 and age matched.

Main Outcome Measures: Bmax (density) of the two receptors and protein and mRNA levels of adenosine receptors were determined in adipose tissue of AAW and CAW.

Results: No differences were found for {alpha}-2 receptor Bmax in either VAT or SAT from AAW and CAW. Bmax (but not the dissociation constant, Kd) for the adenosine A1 receptor in VAT from AAW was higher (P < 0.05) than in VAT from CAW. Adenosine receptor protein and mRNA levels were significantly higher in VAT from AAW than VAT from CAW. No racial differences in these parameters were observed in SAT.

Conclusions: These data suggest that inhibition of lipolysis by adenosine has the potential to be greater in obese AAW, and this could possibly be one explanation for the observation that obese AAW have more difficulty in losing weight than obese CAW.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
OBESE AFRICAN-AMERICAN women (AAW) lose less weight and at a slower rate than Caucasian women (CAW) do across a variety of treatments including conservative interventions (1), very low calorie intake (2, 3), and surgery (4, 5, 6). The racial difference in the response to weight loss treatments remains after adjustment for age and level of education and cannot be entirely attributed to socioeconomic or cultural factors (7, 8, 9, 10). This suggests that there are additional biological differences that contribute to the prevalence of obesity in AAW, but the precise causes that underlie these differences are not fully understood.

Lipolysis of fat is mediated by the enzyme hormone-sensitive lipase (HSL). HSL catalyzes the rate-limiting step of lipolysis by hydrolyzing the stored triacylglycerols and diacylglycerols into fatty acids and glycerol. In the basal state, the rate of lipolysis is low because HSL is relatively inactive, but upon HSL activation the rate of lipolysis is enhanced. Catecholamines bind to the ß-adrenergic receptors on adipocytes and activate HSL through the G protein signaling cascade, the hallmark of which is elevation of intracellular cAMP levels. Several agents including insulin, adenosine, and {alpha}-adrenergic agonists will inhibit the synthesis of cAMP by inhibiting the membrane bound adenylate cyclase. Thus, elevations in the concentration of any of these agents would be expected to reduce lipolysis by not activating HSL.

Reports from our and other laboratories (11, 12, 13) have shown lower rates of in vivo lipolysis in obese AAW, compared with obese CAW. Other studies from our laboratory (14) have shown that stimulated lipolysis was similar in freshly isolated adipocytes from AAW and CAW. Furthermore, we recently reported that densities of ß-adrenergic receptors were higher in visceral adipose tissue (VAT) from obese AAW, compared with CAW (15). Together these findings suggest that the potential for lipolysis might be the same or higher in AAW than CAW (15), but yet in vivo lipolysis is decreased in AAW. These disparate results led us to postulate that in vivo lipolysis might be inhibited in AAW. Several agents, including insulin, {alpha}2-adrenergic agonists, adenosine, and nitric oxide, have been reported to suppress lipolysis in vivo (12, 16, 17, 18, 19, 20, 21, 22). Abnormal lipolysis has been suggested to be linked to obesity and may be partially modulated by adenosine (23). It has been demonstrated that there is an extracellular cAMP-adenosine pathway leading to the production of adenosine by adipocytes (24, 25, 26) and that binding of adenosine to the A1 receptor inhibits lipolysis by adipocytes (27, 28, 29). Identifying the role that any or all of these inhibitors may have in inhibiting lipolysis is important to the understanding of the mechanisms behind the enhanced obesity in the AAW.

This study was initiated to determine whether adenosine or agonists to the {alpha}2-adrenergic receptor might contribute to the putative inhibition of in vivo lipolysis in AAW. To that end, we sought answers to the following questions: is the number or affinity of either the adenosine A1 or the {alpha}2-adrenergic receptors different in VAT and sc adipose tissue (SAT) preparations from obese AAW and CAW? Are the protein mass and mRNA levels of the adenosine A1 receptor different in the adipose tissue from AAW and CAW? Answers to these questions will shed light on the potential mechanisms behind the decrease in lipolysis that leads to the slower rate of weight loss in AAW.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Morbidly obese (body mass index (BMI) > 40 kg/m2) AAW and CAW participated in this study. The participants were nonsmokers, free of vascular disease, diabetes, or cancer and were not taking any adrenergic medications or medications that might affect carbohydrate or lipid metabolism. The subjects were not taking hormone replacement therapy or birth control pills. The women who participated in this study were recruited from the Department of Surgery at the Brody School of Medicine, East Carolina University, and were selected on the basis of BMI according to the guidelines of the World Health Organization. AAW were included in this study only if their parents and grandparents were of African-American descent. Body mass and height were recorded to the nearest 0.1 kg and 0.1 cm, respectively, and the BMI calculated to be above 42 kg/m2 for both the AAW and CAW. Blood was collected the day of the surgery after an overnight fast. Adipose tissue was obtained from all the participants during open abdominal surgery for gastric bypass. VAT was dissected from the greater omentum, and SAT was dissected from the epigastric region of the abdomen. Tissues were frozen in liquid nitrogen, wrapped in foil, and stored at –70 C until time of assay (1–4 wk). Written consent was obtained from all of the subjects after they were informed of the nature of the study. The institutional review board for human subject research approved the protocols used in this study.

Membrane preparations

Membrane preparations were prepared as previously described (15). Briefly, membranes were prepared by thawing and homogenizing 1 g adipose tissue in ice-cold buffer [20 mM HEPES, 150 mM sucrose, 1 mM EDTA (pH 7.4); 1:4 (vol/vol)], containing protease inhibitors (2 µM pepsatin, 2 µM leupeptin, 0.1 mg/ml bacitracin, 100 U/ml aprotinin). The homogenate was filtered through two layers of cheesecloth and centrifuged for 15 min at 1500 x g. The infranatant was collected and centrifuged at 100,000 x g for 1 h. The pellet, which contained the membrane fraction of the adipocytes, was suspended in cold homogenization buffer to a protein concentration of 1 mg/ml and frozen at –70 C until time of assay. Membrane preparations were stable up to 4 months when stored in this manner.

Radioligand binding assays for the adenosine A1 receptor

Binding studies were done as we have previously described (30). Briefly, adipose tissue membrane preparations were rapidly thawed, and adenosine receptor binding was determined using the radioligand 8-cyclopentyl-1, 3-[3H]dipropylxanthine ([3H]DPCPX) to label the receptors. All assays were run in triplicate. For total number of receptors, [maximal binding capacity (Bmax)], 1.0 nM [3H]DPCPX was incubated with 70–150 µg membrane protein (preincubated for 30 min with 0.4 U/µl adenosine deaminase) in 500 µl total volume [buffer: 50 mM Tris, 5 mM MgCl2 (pH 7.4)] for 30 min at 25 C. At the end of the incubation period, the tubes were placed on ice for 10 min, rapidly filtered through Whatman GF/C glass fiber filters, and washed with 18 ml ice-cold incubation buffer. Radioactivity remaining on the filters was quantified using liquid scintillation spectroscopy. Nonspecific binding was determined in the presence of 100 µmol/liter R (-)-N6-phenylisopropyladenosine. Dissociation constant (Kd) values were determined by Scatchard plot analyses using 0.1–2 nM radioligand.

Radioligand binding assays for the {alpha}2-adrenergic receptor

Adipose tissue membrane preparations were rapidly thawed, and Bmax for {alpha}2-adrenergic receptors was determined by using the radioligand [3H]Yohimbine to label the receptors. Briefly, 4.0 nM [3H]Yohimbine was incubated with 40 µg membrane protein in 500 µl total volume [buffer: 50 mM Tris, 5 mM MgCl2 (pH 7.4)] for 15 min at 37 C. At the end of the incubation period, the samples were rapidly filtered through Whatman GF/C glass fiber filters and washed with 15 ml ice-cold incubation buffer. Radioactivity remaining on the filters was quantified using liquid scintillation spectroscopy. Nonspecific binding was determined in the presence of 1 µM phentolamine. Kd values were determined by Scatchard plot analyses using 0.5–4 nM radioligand. IC50 values, measured from competition binding assays displacing with either clonidine or phentolamine, were converted to Kd values according to the method of Cheng and Prusoff (31).

RNA isolation and RT-PCR

Total RNA was isolated from approximately 100 mg adipose tissue with TRIzol reagent (Roche Diagnostics, Indianapolis, IN) according to the manufacturer’s instructions and purified using an RNeasy column (QIAGEN, Valencia, CA). Each column was then washed with a mixture of 70 µl RDD buffer (QIAGEN) and 10 µl DNase I (QIAGEN, 2.7 U/µl) solution to degrade any residual DNA that may have been transferred over. RT-PCR was conducted as described earlier (32, 33). Briefly, for the reverse transcription reaction, 5 µg purified total RNA were reverse transcribed in the presence of an anchored oligo-p (dT)15 primer by use of avian myeloblastosis virus reverse transcription (Roche Diagnostics) based on the manufacturer’s recommendations. Sets of specific primers for adenosine A1 receptors are as follows: primer nucleotides sequence product size (A1 forward 295–314, 5'-TGT CCT CAT CCT CAC CCA GA-3' 310, A1 reverse 586–605, 5'-GCA CCC AGA CGA AGA AGT TG-3' 241).

Protein analysis

Adenosine A1 receptor mass was determined by Western blot analysis as we described earlier (15). Protein from the membrane preparations (20 µg) was mixed with sodium dodecyl sulfate loading buffer and subjected to SDS-PAGE on a 10% gel. Protein content was determined as described by Bradford using BSA as a standard.

Statistics

Comparisons of data were conducted using a Student’s t test when data were normally distributed. For nonhomogeneous data a Mann-Whitney rank sum test was used. Statistical testing was performed using SigmaStat 2.03 (SPSS Inc., Chicago IL). The level of statistical significance for these experiments was P < 0.05. Data are expressed as the mean ± SEM or SD.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The results from this study are presented as follows: 1) data showing the fat-depot (SAT and VAT) differences in the expression of the A1 adenosine receptor; 2) data showing ethnic and fat depot differences in the expression of the A1 adenosine receptor; and 3) data showing fat-depot Bmax of the {alpha}2-adrenergic receptor.

The characteristics of the subjects who participated in the current study are shown in Table 1Go. The two groups of obese women were similar to those we studied previously and did not differ in age, BMI, or fasting plasma glucose or insulin levels (11, 14, 15, 33, 34, 35). Free fatty acid levels were significantly lower in the AAW, and glycerol levels tended to be lower in these subjects, but the difference was not statistically significant.


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  		TABLE 1. Physiological and biochemical characteristics of subjects

 
Table 2Go shows adenosine A1 receptor mRNA and protein levels as well as Bmax of [3H]DPCPX in membrane preparations of SAT and VAT from the participants in the current study. No differences in mRNA levels between SAT and VAT were observed, but both the protein concentration and Bmax were significantly (P < 0.05) higher in the SAT than VAT, indicating higher rates of translation of the gene.


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  		TABLE 2. Adenosine A1 receptors in VAT and SAT

 
Figure 1AGo demonstrates that total apparent adenosine A1 receptor binding was significantly greater in the VAT preparations from AAW when compared with CAW (P < 0.05). When assessing adenosine A1 receptors in SAT, we found no significant differences in apparent numbers of these receptors in preparations from the AAW when compared with CAW (AAW, 12.7 ± 3.3 vs. CAW, 12.8 ± 4.0 fmol/mg protein). Bmax capacity of the adenosine A1 receptor was significantly higher in SAT than VAT from the CAW (P < 0.05). In addition, Kd values for adenosine A1 receptors, determined using saturation curves from VAT and SAT preparations from obese AAW and CAW, showed no racial differences in adenosine A1 receptor affinities in either type of adipose tissue from the obese AAW and CAW (Kd values: AAW, 0.4 ± 0.1 nM vs. CAW, 0.4 + 0.07 nM).


Figure 1
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  		FIG. 1. A, Bmax for adenosine A1 receptors in SAT and VAT preparations from AAW and CAW. Bmax values were significantly higher in the VAT from obese AAW than in the VAT from obese CAW (AAW, n = 9; CAW, n = 8). No significant differences in total apparent numbers of these receptors were found in SAT preparations from the AAW when compared with CAW (AAW, n = 4; CAW, n = 4). Bmax values were significantly higher in SAT than VAT in the obese CAW. *, AAW VAT, compared with CAW VAT (P < 0.05); **, CAW VAT, compared with CAW SAT (P < 0.05). B, Adenosine A1 receptor protein mass determined by Western blot analysis in SAT and VAT preparations from AAW and CAW. Protein levels (normalized) for adenosine A1 receptors in VAT from obese AAW were significantly higher than those from CAW (AAW, n = 7; CAW, n = 8). In the SAT preparations, no significant racial differences were seen in the adenosine A1 receptor mass (AAW, n = 7; CAW, n = 7). Protein concentration (mass) was significantly higher in SAT than VAT from CAW. Y-axis values are arbitrary units as described in Subjects and Methods. *, AAW VAT, compared with CAW VAT (P < 0.05); **, CAW VAT, compared with CAW SAT (P < 0.05). C, Adenosine A1 mRNA in SAT and VAT preparations from AAW and CAW. Total mRNA levels of adenosine A1 receptors, normalized to ß-actin, in VAT were significantly higher in obese AAW when compared with CAW. (AAW, n = 9; CAW, n = 8). No significant differences were found between AAW and CAW mRNA levels for the adenosine A1 receptor in sc adipose tissue (AAW, n = 8; CAW, n = 10). In AAW, mRNA levels were significantly lower in SAT when compared with VAT. Y-axis values are arbitrary units as described in Subjects and Methods. *, AAW VAT, compared with CAW VAT (P < 0.05); **, AAW VAT, compared with AAW SAT (P < 0.05).

 
Adenosine A1 receptor protein mass was significantly higher (P < 0.05) in VAT of AAW than that in CAW as shown in Fig. 1BGo but not different in SAT preparations from the two groups (AAW 2.0 ± 0.3 vs. CAW, 3.0 ± 0.7). Protein concentration was significantly higher in SAT than VAT of the CAW but not AAW (P < 0.05).

Differences in the expression of the A1 adenosine receptor in SAT and VAT of obese AAW and CAW are shown in Fig. 1CGo. Total apparent mRNA levels for adenosine A1 receptors, normalized to ß-actin, in VAT were significantly higher (P < 0.05) in obese AAW than CAW. No significant differences were found between AAW and CAW in mRNA levels for the adenosine A1 receptor in SAT (AAW: 0.52 ± 0.07 vs. CAW, 0.67 ± 0.15). In AAW, but not CAW, mRNA levels were significantly lower in SAT when compared with VAT (P < 0.05).

Total apparent numbers of {alpha}2-adrenergic receptors (Bmax) were found not to be significantly different in tissues from either VAT or SAT preparations derived from obese AAW and CAW (Fig. 2Go). Because we did not see any receptor Bmax differences, we did not pursue further investigation of receptor protein or mRNA levels for the {alpha}2-receptor.


Figure 2
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  		FIG. 2. Bmax for {alpha}2-adrenergic receptors in SAT and VAT preparations from AAW and CAW. No significant differences in total apparent numbers of {alpha}2-adrenergic receptors were found in either SAT or VAT preparations from obese AAW when compared with obese CAW (AAW, n = 8; CAW, n = 7).

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The current study yielded several novel findings. The first is the demonstration that whereas there were no differences in the mRNA levels of the adenosine A1 receptor between SAT and VAT, both receptor protein mass and receptor Bmax were significantly higher in SAT than VAT. These differences in the expression of the receptor indicate that processes that are influenced by adenosine, such as inhibition of lipolysis, would be more responsive in SAT than VAT. This would suggest that under conditions that favor fat mobilization, loss of fat from SAT would be less than from VAT.

Other novel findings include: 1) higher mRNA levels, protein mass, and adenosine A1 receptor numbers in VAT from AAW when compared with VAT from CAW; 2) lack of racial differences in these parameters in SAT from the two groups of women; and 3) functional similarity of the adenosine A1 receptor in the AAW and CAW because Kd values were not altered (see Results). Together these data indicate that responsiveness to the effects of adenosine would be comparable in the SAT of both AAW and CAW, but responsiveness to adenosine in the VAT would be more pronounced in the AAW than the CAW.

These observations tempt us to speculate the following: because of the overexpression of the adenosine A1 receptor in the VAT of the AAW, in vivo fat mobilization from VAT of the AAW would be lower than that from VAT of the CAW. This postulate is supported by experimental evidence. Data from the current study showing decreased levels of free fatty acids in the fasted state (Table 1Go) are consistent with the concept of reduced in vivo lipolysis in the AAW. Additionally, in a recent study, Nicklas et al. (36) measured several parameters before and after 6 months of a hypocaloric diet and low-intensity walking in obese postmenopausal AAW and CAW. They found that the absolute amount of body weight lost was similar in the AAW and the CAW. However, AAW lost less fat mass than the CAW. Both groups decreased their sc abdominal fat, but the CAW decreased their visceral fat area, whereas the AAW did not (36). In another report, the beneficial effects of dieting and exercise in overweight premenopausal AAW and CAW were examined by Gower et al. (37). The CAW lost significantly more visceral fat and less sc abdominal fat than did the AAW despite similar weight loss.

These studies indicate that during weight loss and exercise, physiological conditions in which stress hormone levels are high, mobilization of visceral fat is less efficient in the AAW than the CAW, which results in a lower loss of visceral fat in the AAW than the CAW. Furthermore, we have previously shown that apparent numbers of ß-adrenergic receptors are higher in VAT from AAW when compared with CAW (15), and others have demonstrated that extracellular levels of adenosine rise during ß-receptor activation (38). Therefore, activation of the increased numbers of ß-receptors in the AAW VAT could contribute to increased levels of adenosine in this tissue. This increased amount of adenosine, as well as the increased number of adenosine receptors in VAT from AAW when compared with VAT from CAW, suggests that lipolysis inhibition in VAT of obese AAW women would be more prominent than in obese CAW.

These reports, along with our present findings, would reignite the controversial issue regarding body fat distribution in obese AAW and CAW. Some studies (39) suggest that AAW are more obese and have more VAT than obese CAW, whereas other studies (40, 41) suggest that obese AAW have less visceral fat than CAW. Our findings, which suggest higher potential for inhibition of lipolysis in AAW VAT, would favor the concept that AAW would be expected to have a larger visceral fat compartment than CAW of similar weight.

Identifying the role of various in vivo antilipolytic agents in AAW is important to the understanding of why AAW lose weight at a slower rate than CAW. Our final novel finding that {alpha}2-adrenergic receptor densities are not different in VAT and SAT from obese AAW and CAW rules out {alpha}2-adrenergic receptors as contributing factors to the decreased lipolysis in AAW.

It should be noted here that our findings, which demonstrate increases in transcription, translation, and density of the adenosine A1 receptor in VAT from AAW, were obtained from in vitro studies of isolated plasma membranes. It is important to mention here that to fully understand the biological significance of these differences, the rate of stimulated lipolysis in freshly isolated adipocytes from VAT and SAT of AAW and CAW needs to be tested in the presence and absence of adenosine. Furthermore, in vivo studies of fatty acid turnover in the obese AAW and CAW are also needed to ascertain the importance of the in vitro findings. However and despite these limitations, our results, demonstrating an increase in A1 receptors, which in turn can exacerbate inhibition of lipolysis in VAT, shed light on potential causes behind the lesser and slower rate of weight loss of obese AAW. These findings might be helpful in designing new strategies for the control and prevention of obesity in AAW and other women as well.


   Footnotes
 
This work was supported in part by a grant from the American Diabetes Association and supported in part by Heart, Lung and Blood Institute, National Institutes of Health, Grant HL-27339.

Author disclosure summary: H.B., J.D., D.L., S.J.M., and M.M.M. have nothing to declare.

First Published Online February 28, 2006

Abbreviations: AAW, African-American women; Bmax, maximal binding capacity; BMI, body mass index; CAW, Caucasian women; [3H]DPCPX, [3H]dipropylxanthine; HSL, hormone-sensitive lipase; Kd, dissociation constant; SAT, sc adipose tissue; VAT, visceral adipose tissue.

Received September 23, 2005.

Accepted February 16, 2006.


   References
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 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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