Differences in β-adrenergic receptor densities in omental and subcutaneous adipose tissue from obese African American and Caucasian women

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  Differences in β-adrenergic receptor densities in omental and subcutaneous adipose tissue from obese African American and Caucasian women
  Differences in   -Adrenergic Receptor Densities in Omental and SubcutaneousAdipose Tissue From Obese African American and Caucasian Women Mona M. McConnaughey, Kathryn Ann Sheets, Julianne Davis, Jonathan Privette, Robert Hickner,Brandon Christian, and Hisham Barakat AfricanAmericanwomenloselessweightandataslowerratethanCaucasianwomenunderthesameweightlossconditions.This is likely due to decreased mobilization of fat, possibly involving differences in the responsiveness of adipose tissue toadrenergic stimulation. To better understand the causes behind the decreased lipolysis in African American women, thisstudy was initiated to determine if there were differences in the numbers and affinities of    adrenoreceptors in omental andsubcutaneous adipose tissue of obese African American and Caucasian women. We determined the number of    receptorsusing a nonselective antagonist and found the total number of receptors in both omental and subcutaneous adipose tissuepreparations were higher in African American than Caucasian women.  1,  2 , and  3  densities were higher in omental adiposetissue ( P  < .05), but not different in the subcutaneous tissue of the African American women. No racial differences in kd valuesfor adrenergic agents (agonists and antagonists) were found with regard to   1 ,   2 , or   3  receptors in either the omental orthe subcutaneous preparations.   1  and   2  receptor protein (mass) was significantly increased in African American omentaltissue preparations, but not subcutaneous. Our in vitro data demonstrating increased    receptor numbers in omental tissuefrom obese African Americans suggest that the potential for lipolysis would be higher in these women. Future studies shoulddetermine the biologic significance of the differences in the    adrenergic receptors in vivo. ©  2004 Elsevier Inc. All rights reserved. A FRICAN AMERICAN women have a tendency to gainweight at an earlier age and to be heavier than Cauca-sians of a similar age. 1,2 In addition to their propensity for agreater weight gain, obese African American women lose lessweight and lose weight at a slower rate than Caucasians acrossa variety of treatments including conservative interventions, 3 very low calorie diet, 4,5 and surgery. 6-9 The racial difference inweight gain and the response to weight loss treatments remainsafter adjustment for age and level of education and cannot beentirely attributed to socioeconomic or cultural factors. 10-13 This suggests that there are additional biologic differences thatcontribute significantly to the prevalence of obesity in AfricanAmerican women, but the precise causes that underlie thesedifferences are not fully understood.The mobilization of fat from adipose tissue stores is medi-ated by the enzyme hormone sensitive lipase (HSL). HSLcatalyzes the first step of lipolysis by hydrolyzing the storedtriacylglycerols and diacylglycerols to fatty acid and glycerol.In the basal state, the rate of lipolysis is low because HSL isrelatively inactive, but upon HSL activation, the rate of lipol-ysis is enhanced. Catecholamines bind to    receptors on adi-pocytes and activate HSL through the G-protein signalingcascade. Insulin and other agents counter-regulate lipolysis byactivation of phosphodiesterase, which leads to a decrease inthe concentration of the G-protein signaling cascade interme-diate, cyclic adenosine monophosphate (cAMP).We have previously reported that the concentrations of glyc-erol and free fatty acids in fasting plasma of obese AfricanAmerican women were significantly lower than those of obeseCaucasian women, consistent with other reports of lipolysisbeing lower in African Americans than Caucasians. 14-16 Wealso reported that HSL mass was decreased, but activity (ex-pressed/milligram protein) was not different in the adiposetissue of the African American women. Thus, the decreasedbasal lipolysis could be partly due to the decrease in HSL mass.We followed these observations by determining the rate of lipolysis under catecholamine stimulation of adipose tissue invitro. Our previous findings demonstrated that isoproterenol-stimulated lipolysis reached the same maximal level in bothraces, but because of a lower basal HSL, the African Americanwomen showed increased stimulated lipolysis when expressedas fold stimulation. 16 The results from our previous study led us to postulate thatthe stimulation of lipolysis by isoproterenol in the adiposetissue of the African American women could possibly be due todifferences in the individual steps of the lipolytic cascade thatlead to HSL activation or an increased number or affinity of   -adrenergic receptors. Thus, this study was initiated to definethe underlying mechanisms that modulate these racial differ-ences of in vitro lipolysis. We measured   -adrenergic receptordensities and affinities, as well as protein mass in both omentaland subcutaneous adipose tissue preparations of obese AfricanAmerican and Caucasian women. The results of these studieswill help to better define the mechanisms behind the decrease inlipolysis that leads to the slower rate of weight loss in AfricanAmerican women. MATERIALS AND METHODS Subjects Morbidly obese (body mass index [BMI]    40) African American(n  15) and Caucasian (n  21) women participated in this study. Theparticipants were free of vascular disease, diabetes, or cancer and werenot taking any adrenergic medications or medications that might affectcarbohydrate or lipid metabolism. The subjects were not taking hor- From the Departments of Medicine, Pharmacology, and Physiology, Brody School of Medicine, East Carolina University, Greenville, NC.Submitted June 28, 2003; accepted September 27, 2003.Supported in part by a grant from the American Diabetes Associa-tion. Address reprint requests to Hisham Barakat, PhD, Department of  Medicine, Brody School of Medicine, East Carolina University,Greenville, NC 27858. ©  2004 Elsevier Inc. All rights reserved.0026-0495/04/5302-0017$30.00/0doi:10.1016/j.metabol.2003.09.014 247 Metabolism,  Vol 53, No 2 (February), 2004: pp 247-251  mone replacement therapy or birth control pills. The women whoparticipated in this study were recruited consecutively over a period of 18 months 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.African American women were included in this study only if theirparents and grandparents were of African American descent. Age(years) of African Americans was 42  2 and 44  2 for Caucasians.Body mass and height were recorded to the nearest 0.1 kg and 0.1 cm,respectively and the BMI calculated to be 44    4 and 50    3,respectively, for the African American and Caucasian women. Glucosevalues (mg/dL) were 94    3 for African American and 97    5 forCaucasian women. Insulin values (  U/mL) were 7.2  1.1 and 7.4  2, respectively, for African American and Caucasian women. Triglyc-erides (mg/dL) were 89    1 and 129    2, respectively, for AfricanAmerican and Caucasian women. Free fatty acid values (  mol/L) were522  10 for African American and 847  41 for Caucasian women.Adipose tissue was obtained from the volunteers during abdominalsurgery for gastric bypass or total abdominal hysterectomy. Omentaladipose tissue was dissected from the greater omentum and subcuta-neous tissue 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 to 4 weeks). Written consent was obtainedfrom all of the subjects after they were informed of the nature of thestudy. The Institutional Review Board for human subject researchapproved the protocols used in this study.  Membrane Preparations Membrane preparations were prepared by thawing approximately 1 gomental adipose tissue and homogenizing this (glass on glass tissuehomogenizer) in ice cold buffer (20 mmol/L HEPES, 150 mmol/Lsucrose, 1 mmol/L EDTA, pH 7.4; 1:4 vol/vol), containing proteaseinhibitors (2   mol/L pepsatin, 2   mol/L leupeptin, 0.1 mg/mL baci-tracin, 100 U/mL aprotinin). The homogenate was filtered through 2layers of cheesecloth and centrifuged for 15 minutes at 1,500  g . Theinfranatant was collected and centrifuged at 100,000    g  for 1 hour.The pellet, which contained the membrane fraction of the adipocytes,was suspended in cold homogenization buffer to a protein concentra-tion of 1 mg/mL and frozen at  70°C until time of assay. Membranepreparations were stable up to 4 months when stored in this manner.  Radioligand Binding Assay Membrane preparations of adipose tissue from the African Americanand Caucasian women were rapidly thawed and maximal binding capacity(Bmax) was determined by the use of   125 I-labeled cyanopindolol ( 125 I-CYP), a  adrenergic antagonist, to label the receptors. 17 Briefly,  125 I-CYP(60 pmol/L for   1  and   2  receptors or 350 pmol/L for   3  receptors) wasincubated with 30 to 40   g membrane protein in 200   L total volume(buffer: 50 mmol/L Tris, 5 mmol/L MgCl 2 , pH 7.4) for 30 minutes in a37°C shaking water bath. At the end of the incubation period, the tubeswere placed on ice for 10 minutes, rapidly filtered through Whatman GF/Cglass fiber filters (Maidstone, UK), and washed with 12 mL ice coldincubation buffer. Nonspecific binding was determined in the presence of 10  7 mol/L of the  1  antagonist, CGP20712A (Ciba Geigy, Tom’s River,NJ) for   1  receptors, the   2  antagonist ICI 118551 (ICI) for   2  receptors,and the   3  antagonist L-748337 (Merck, Whitehouse Station, NJ) for   3 receptors. 18 For the nonspecific blockade of total    receptor binding, weused 10  5 mol/L propranolol (Eli Lilly, Indianapolis, IN). Radioactivityremaining on the filters was quantified using a Beckman 5500 Gammacounter (Fullerton, CA). Displacement curves were generated using  125 I-CYP to label the receptors with increasing concentrations of     adrenergicagents (10  10 mol/L to 10  6 mol/L). For the  3  receptor assay, the Merck compound L-748337 was dissolved in 50% dimethyl sulfoxide (DMSO).The final concentration of DMSO in the reaction mixture for both total andnonspecific binding tubes was 0.5% that has been shown to have no effecton the binding to the   3  adrenergic receptor. 18 Total apparent numbers of receptors were calculated using both a previously determined saturatingconcentration of   125 I-CYP (60 pmol/L for   1  and   2 , 350 pmol/L for   3 )and/or from Scatchard plot analyses. 19 Kd values were derived fromScatchard plot analyses, 19 saturation binding isotherms, and/or displace-mentcurves.IC 50  values,measuredfromcompetitionbindingassays,wereconverted to kd values according to the method of Cheng and Prusoff. 20 The antagonists, CGP 20712A, ICI 118551, L748337 and the agonists,dobutamine, terbutaline, CGP12177 were used to displace  125 I-CYP off of the   1 ,  2 , and   3  receptors, respectively.  Immunoblot Analysis  1 ,   2 , and   3  receptor mass was determined by Western blotanalysis. 21 Protein from the membrane preparations (20   g) was mixedwith sodium dodecyl sulfate (SDS) loading buffer and subjected toSDS-polyacrylamide gel electrophoresis (PAGE) on a 10% gel. Proteincontent was determined as described by Bradford 21 using bovine serumalbumin (BSA) as a standard. Proteins were electrotransferred onto anitrocellulose membrane (Bio-Rad, Hercules, CA).   1 -adrenergic re-ceptor (AR) was detected with a rabbit polyclonal antibody (IgG-A20)raised against the C-terminus of human   1-AR.   2 -AR was detectedwith a rabbit polyclonal antibody (IgG-H20) raised against the C-terminus of human   2 -AR.   3 -AR was detected with a goat polyclonalantibody (IgG-C20) raised against the C-terminus of human  3 -AR. Allprimary antibodies were used at 1.25   g/mL, and detection of signalswas performed using the SuperSignal West Pico ChemiluminescentSubstrate kit (Pierce, Rockford, IL). Antirabbit horseradish peroxidase-conjugated IgG was used as secondary antibody for anti-  1 -AR andanti-  2 -AR. Antigoat horseradish peroxidase-conjugated IgG was usedas secondary antibody to anti-  3 -AR. All antibodies were purchasedfrom Santa Cruz Biotechnology (Santa Cruz, CA). A random samplewas picked to serve as a control and run with each gel. After quanti-fication on a phosphorimager, the sample was assigned a value of 1.0and ratios were obtained by comparison with each sample. Statistics Comparisons of data were conducted using a Student’s  t   test when datawere normally distributed. For nonhomogeneous data, a Mann-WhitneyRankSumtestwasused.StatisticaltestingwasperformedusingSigmaStat2.03 (SPSS, Chicago IL). The level of statistical significance for theseexperiments was  P  .05. Data are expressed as the mean  SEM. RESULTS To determine the underlying causes behind the differencebetween the African American and Caucasian women withrespect to fold stimulation by isoproterenol, we measured max-imal binding (Bmax) of   125 I-CYP to membranes of subcutane-ous and omental adipose tissue from African American andCaucasian women. As seen in Fig 1, this total, nonselective  -receptor binding was significantly greater in both the subcu-taneous and omental preparations from African Americanwomen ( P    .05). To further define these changes, we mea-sured   1 ,   2 , and   3  subtypes in the 2 types of adipose tissuefrom the African American and Caucasian women. As seen inFig 2, there was a significant increase in apparent   1 ,   2 , and  3  adrenergic receptor numbers in the African American omen-tal tissue when compared with Caucasian tissue ( P    .05).When assessing    receptors in subcutaneous tissue, we foundno significant differences in apparent   1 ,   2 , or   3  receptors inpreparations from the African Americans when compared withCaucasians (Fig 3). The summation of the 3 subtypes of    248 M C CONNAUGHEY ET AL  receptor densities for both omental and subcutaneous fat (Figs2 and 3) is less than the total    receptor numbers depicted inFig 1, in which we quantitated the total receptor density usingthe nonselective displacing agent, propranolol. This can possi-bly be explained by the fact that although  125 I-CYP is relativelyselective for    receptors, it can label other receptors, as well,particularly at the concentration of 350 pmol/L. In addition todisplacing  125 I-CYP from the    receptors, propranolol (10  5 mol/L) may be displacing the  125 I-CYP from other receptors,thus giving us a slightly elevated value.We found   -receptor protein mass to be significantly in-creased for   1  and   2  receptors in omental preparations fromAfrican American women as shown in Table 1. Although   3 receptor mass appeared to be increased in omental tissues fromthe obese African Americans, significance was not achieved. Inthe subcutaneous adipose tissue preparations, we found noracial differences in the  -receptor mass for all 3 of the receptorsubtypes (Table 1).Kd values for   1 ,   2 , and   3  adrenergic agents were deter-mined in omental adipose tissue (Table 2) and subcutaneoustissue (Table 3) from obese African American and Caucasianwomen. Values were determined for the 3 subtypes of receptorsusing saturation curves, displacement curves, and/or Scatchardanalyses. In both the subcutaneous and omental tissue prepa-rations, no racial differences in receptor affinities were foundbetween obese African American and Caucasian women. DISCUSSION The results of this study produced the novel findings that  -adrenergic receptor densities and protein mass are increased Fig 1. Total apparent  adrenergic receptor numbers (Bmax) weredetermined in tissue from obese African American (AA) and Cauca-sian (C) women using  125 I-CYP (350 pmol/L) to label the    receptorsas described in Materials and Methods (n    10). The nonselectiveantagonist, propranolol (10  5 mol/L) was used to determine nonspe-cific binding. Total apparent    receptor numbers were significantlyincreased in both subcutaneous and omental adipose membranepreparations from obese African American women when comparedwith preparations from Caucasian women. *Statistically significant( P  < .05).Fig 2. Total apparent   1 ,   2 , and   3  adrenergic receptors weredetermined in omental tissue from obese African American (AA) andCaucasian (C) women as described in Materials and Methods (  1 ,   2 n  9 (AA) and n  12 (C);   3  n  9).   1 ,   2 , and   3  receptor densitieswere significantly increased in the African American preparationswhen compared with Caucasian. *Statistically significant ( P  < .05).Fig 3. Total apparent   1 ,   2 , and   3  adrenergic receptors weredetermined in subcutaneous tissue from obese African American(AA) and Caucasian (C) women as described in Materials and Meth-ods (  1 ,  2  n  8;  3  n  12). No significant differences in  1,  2 , or  3 receptor densities were seen in the African American preparationswhen compared with Caucasian.Table 1.   -Receptor Mass in Omental and Subcutaneous AdiposeTissue Preparations From Obese African Americanand Caucasian Women Omental SubcutaneousReceptorSubtypesAfricanAmerican CaucasianAfricanAmerican Caucasian  1  0.88  0.09* 0.69  0.04 0.84  0.06 0.93  0.06  2  0.76  0.04* 0.48  0.03 0.60  0.10 0.69  0.07  3  0.80  0.09 0.65  0.11 0.77  0.07 0.67  0.08NOTE.   -receptor mass is expressed in arbitrary units that werenormalized to 1 value obtained from including the sample on all gels.Values are mean  SEM, (n  8 to 12).   1 -and   2 -receptor mass wassignificantly higher in omental tissue from obese African Americans.*Statistically significant ( P   .01).249ADRENERGIC RECEPTORS IN BLACKS AND WHITES  in omental tissue from obese African American women whencompared with Caucasian. Because kd values were not alteredfor either agonists or antagonists, this suggests that the recep-tors are functionally similar in the African Americans andCaucasians. These results are consistent with our previousfindings demonstrating that in vitro isoproterenol-stimulatedlipolysis reached the same maximal level in both races, despitea lower HSL mass in the adipose tissue of African Americanwomen. 21 This decrease in mass of HSL explains the lower invitro basal lipolytic rate by adipose tissue from the AfricanAmericans. When this is taken into consideration, the foldstimulation of lipolysis in the obese African American womenis higher than that of the Caucasian women. Our findings thatkd values were not significantly different for any of the adren-ergic agents investigated between the 2 races in either type of adipose tissue suggest that the racial differences we see in vitrowith regard to enhanced fold stimulation are related primarilyto increases in   -receptor densities.There are a variety of biochemical differences betweenomental and subcutaneous adipose tissues. 22-27  -receptor den-sity and lipolysis are both higher in omental fat when comparedwith subcutaneous fat. 28 Also, catecholamines seem to be morelipolytic in omental fat cells than in subcutaneous cells. 28 Interestingly, our current findings showed the same trends inthe tissue preparations from African American women, and thedifferences in all 3    subtypes are more pronounced in theomental adipose tissue.Collectively, our data show that the capacity of omentaladipose tissue to mobilize fat in vitro is higher in AfricanAmerican women than Caucasian women. This is in contrast tothe observation that African American women do not mobilizefat in vivo as effectively. It appears that there are endogenousbiochemical differences in the capacity of adipose tissue of African American women to deposit and mobilize fat that mayexacerbate their obesity. Both the differences and the underly-ing mechanisms need to be further investigated and defined.Studies are needed to determine the lipolytic responsiveness of individual adipose cells to selective    agonists in both omentaland subcutaneous fat from African American and Caucasianwomen. A variety of agents are known to inhibit lipolysis invivo.   2  adrenoreceptor agonists, insulin, adenosine, and nitricoxide have all been reported to suppress lipolysis in vivo. 29-34 Identifying the role that any or all of these inhibitors may havein inhibiting lipolysis in vivo in the African America womenwould be useful. Another area that warrants further investiga-tion deals with receptor polymorphisms.   -adrenergic receptorpolymorphisms have been implicated in a variety of obesitystudies, 35-38 and it is certainly possible that certain polymor-phisms found in African American women could influence thelipolysis. Further studies will help to explain why obese Afri-can American women tend to be more obese and have lesssuccess losing weight than obese Caucasian women and may behelpful in designing strategies for the control and prevention of obesity not only in African American, but also in Caucasianwomen. ACKNOWLEDGMENT We thank Merck for their help and technical assistance and forproviding the   3  antagonist, L-748337 REFERENCES 1. Burke GL, Bild DE, Hilner JE, et al: Differences in weight gainin relation to race, gender, age and education in young adults: TheCARDIA Study. Ethn Health 1:327-335, 19962. Burke GL, Sprafka JM, Folsom AR, et al: Trends in coronaryheart disease mortality, morbidity, and risks factors from 1960 to 1986:The Minnesota Heart Survey. Int J Epidemiol 18:S73-S81, 1989(suppl)3. Kumanyika SR, Obarrzanek E, Stevens VJ, et al: Weight-lossexperience of black and white participants in NHLBI-sponsored clin-ical trials. Am J Nutr 53:1631S-1638S, 1991 Table 3. Kd Values for Adrenergic Agents in SubcutaneousAdipose Tissue Preparations From Obese African Americanand Caucasian Women Receptor Subtype African American Caucasian  1 CGP 20712A 6.1  0.1 nmol/L 4.0  2.0 nmol/LDobutamine 0.9  0.5   mol/L 0.9  2.0   mol/L  2 ICI 118551 0.9  0.1 nmol/L 1.3  0.8 nmol/LTerbutaline 1.7  0.4   mol/L 5.5  1.5   mol/L  3 L-748337 2.5  0.5 nmol/L 5.0  3.0 nmol/LCGP 12177 1.0   mol/L* 1.0   mol/L*NOTE. Kd values were determined for various adrenergic agents byScatchard analyses, saturation curves, and/or competition bindingcurves in African American and Caucasian subcutaneous prepara-tions for each of the   -receptor subtypes. Binding curves were per-formedonpreparationsof4pooledsampleseach(n  2to4(AA),n  2 (C)). No racial differences were found with regard to kd values forany of the subtypes of receptors. Values are expressed asmean  SEM.*One pooled sample comprised of 6 patient tissues. Table 2. Kd Values for Adrenergic Agents in Omental AdiposeTissue Preparations From Obese African Americanand Caucasian Women Receptor Subtype African American Caucasian  1 CGP 20712A 8.6  1.3 nmol/L 10.8  2.2 nmol/LDobutamine 7.3  1.1   mol/L 5.6  2.1   mol/L  2 ICI 118551 7.1  0.9 nmol/L 9.5  1.6 nmol/LTerbutaline 8.5  0.5   mol/L 8.0  0.3   mol/L  3 L-748337 3.3  1.2 nmol/L 2.9  0.9 nmol/LCGP 12177 1.4  0.7   mol/L 2.0  1.0   mol/LNOTE. 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