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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 9 4457-4463
Copyright © 2004 by The Endocrine Society

Postprandial Ghrelin Is Elevated in Black Compared with White Women

Kimberly A. Brownley, Kathleen C. Light, Karen M. Grewen, Edith E. Bragdon, Alan L. Hinderliter and Sheila G. West

Departments of Psychiatry (K.A.B., K.C.L., K.M.G., E.E.B.) and Medicine (A.L.H.), University of North Carolina, Chapel Hill, North Carolina 27599-7175; and Department of Biobehavioral Health (S.G.W.), Pennsylvania State University, University Park, Pennsylvania 16802

Address all correspondence and requests for reprints to: Kim Brownley, Ph.D., Department of Psychiatry, CB #7175, University of North Carolina, Chapel Hill, North Carolina 27599-7175. E-mail: kim_brownley{at}med.unc.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Ghrelin, a gut-brain peptide that signals hunger, is normally suppressed after meals. Subnormal suppression of postprandial ghrelin, previously noted in obese, insulin-resistant individuals, may contribute to increased food intake. Given the ethnic disparities in obesity and obesity-related cardiovascular morbidity in the United States, the present study compared a single postprandial ghrelin measure in 43 women (22 white, 21 black). Each completed a rigorously controlled 4-d dietary intervention designed to maintain weight and constant daily sodium and potassium intake (220 mEq Na, 40 mEq K). Two hours after consuming a test meal of identical content, blood samples were drawn to assess postprandial ghrelin, leptin, and norepinephrine; resting cardiovascular function was measured; and a 24-h urinary cortisol sample was obtained. Independent of body mass index, postprandial ghrelin was significantly higher in black vs. white women, and higher ghrelin was associated with higher cortisol in blacks, who failed to show the expected inverse relation between ghrelin and central obesity seen in whites. Higher ghrelin was correlated with higher blood pressure but lower norepinephrine in obese women. These findings suggest subnormal postprandial ghrelin suppression (or faster ghrelin rebound) in black women, especially the obese, that might play a role in their increased prevalence of obesity and cardiovascular disorders.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
GHRELIN IS AN endogenous ligand of the GH secretagogue receptor and is a potent stimulator of GH secretion (1). Ghrelin is produced primarily in the stomach, but its other sites of origin include the hypothalamus, kidney, heart, and pancreatic ß-cells (2). Ghrelin has both orexigenic and adipogenic effects, thus earning it the label, the hunger hormone, and implicating it in energy homeostasis (1, 3, 4, 5, 6). Acute central and peripheral administrations of ghrelin stimulate food intake, and plasma ghrelin levels increase shortly before and decrease precipitously after food intake (7, 8) in a manner that may be insulin dependent (7, 9). Chronic under- and overfeeding increase and decrease ghrelin, respectively (10, 11, 12); thus, the prevailing ghrelin level tends to be inversely related to relative body weight (13, 14, 15, 16, 17). Ghrelin also exerts cardiovascular and hemodynamic effects, in part, by its actions on the heart and kidney (18, 19, 20, 21). Given its relationships with body mass, eating behavior, insulin, and cardiovascular and renal function, ghrelin’s role in obesity and obesity-related disease has garnered much recent attention.

Obesity is a growing epidemic in the United States, and recent projections indicate obesity will soon surpass smoking as the number one preventable cause of cardiovascular-related death in our society (22). According to the Centers for Disease Control and Prevention (23) surveillance statistics, from 1991 to 2000, obesity increased 61% among U.S. adults, with the major burden of that increase evident in non-Hispanic blacks (12% increase), compared with non-Hispanic whites (8% increase). Overall, blacks are approximately 1.6 times more likely to be obese than whites. Obesity is related to multiple cardiovascular disease risk factors (24, 25, 26, 27), and black women, who suffer higher rates of obesity, hypertension, and diabetes, for example, than their white female counterparts (28), may be especially vulnerable.

To our knowledge, differences in ghrelin level as a function of race have not been investigated. Postprandial ghrelin is of special interest because those individuals who fail to maintain suppression of ghrelin release after a meal may be more susceptible to eating again soon. Furthermore, study designs that control not just a single meal but also all meals for an extended period before testing can provide a more naturalistic assessment of postprandial ghrelin dynamics. Therefore, the purpose of the present study was to examine ghrelin, and its relation to markers of cardiovascular and metabolic function, in a biracial sample of women who were tested after 4 d on the same controlled diet.


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

This study is based on 43 women, 21 black and 22 white, aged 36–63 yr, who participated in a study of dietary sodium and blood pressure, which was approved by the local Biomedical Ethics Committee. Six women were prehypertensive or had stage 1 hypertension (based on resting laboratory readings consistently exceeding 130/85 mm Hg), but none of the 43 women were taking any antihypertensive medications, and all were otherwise healthy. Seventeen women were premenopausal; 26 were postmenopausal (13 with and 13 without current hormone replacement).

Procedures

Dietary intervention. Each participant initially completed a 4-d carefully controlled dietary intervention, during which she maintained her usual daily activities and visited the Clinical Research Center every 24–48 h to eat breakfast and pick up food and beverages for outpatient consumption. Meals were selected and prepared to maintain correct daily electrolyte and nutrient levels by the Clinical Research Center nutritionists. All meals, snacks, and beverages were provided for two alternating daily menus of familiar whole foods to achieve the desired levels (~60% carbohydrate, 28% fat, 12% protein; 220 mEq Na, 40 mEq K). Total caloric load was adjusted for body size (i.e. higher calorie content meals were available to heavier individuals) to prevent larger persons from entering a state of negative energy balance, and pre- vs. postdiet weight comparisons verified that no weight loss occurred. Participants were limited to one cup of caffeinated coffee per day and were instructed to refrain from use of caffeine and any medications on the day of testing. Collections of 24-h urinary sodium and potassium excretion were measured on d 4 and compared with gender- and race-based norms for creatinine clearance to assess dietary compliance. Compliance rates were very high (>97%), in part, because subjects were offered a substantial monetary bonus for full compliance.

On d 4, participants completed a laboratory test session that began between 1630 and 1830 h and lasted 4.5 h. After arriving at the laboratory, they consumed a standardized dinner and underwent a 2-h period of rigidly controlled water drinking and urine collection to promote a steady state of hydration and sodium excretion. During this 2-h stabilization period, they were required to drink 1.5 liters of water and void four times on a fixed schedule. Instrumentation and standardization occurred during this time period. After stabilization, three experimental periods occurred: baseline, continuous mental stress, and recovery, each 40 min in length. Data reported in this paper were obtained at the midpoint of the baseline rest period (i.e. 2 h after ingestion of the standardized meal was complete).

Cardiovascular measures. Cardiac performance was measured using impedance cardiography, and blood pressure (BP) was determined every other minute during min 11–19 of the baseline rest (29, 30, 31), as previously described. Briefly, stroke volume (SV) was derived using the Kubicek equation (32), heart rate was determined from the mean interbeat interval, and cardiac output and total peripheral resistance were calculated using standard formulas (33). To remove the influence of differences in body size on these measurements, cardiac output, SV, and total peripheral resistance were indexed for body size (33) and are hereinafter referred to as cardiac index, SV index, and vascular resistance index. Auscultatory BP was assessed using an automated monitor with R-wave gating, which provides accurate measurements within ± 2 mm Hg between 0 and 300 mm Hg (model 4240, SunTech Medical Instruments, Raleigh, NC).

Bioassays. Blood samples for plasma measures were drawn into prechilled, EDTA-containing tubes at 140 min from the start of the protocol, 120 min after the subjects finished eating the standardized meal and the initial controlled water drinking. These tubes were rapidly cold centrifuged and the resulting plasma pipetted and frozen at –80 C within minutes of collection.

Plasma levels of active acylated ghrelin were measured by a competitive enzyme immunoassay (Peninsula Labs, Belmont, CA). The sensitivity of this assay is 0.08 ng/ml with a standard range of 0–25 ng/ml. The intra- and interassay variation is 5 and 14%, respectively. Total (bound and free) leptin was measured in unextracted plasma by competitive enzyme immunoassay (Peninsula Labs) using a two-step enzyme color generation system to determine relative binding of biotinylated leptin conjugate (competitive ligand) vs. the sample peptide on leptin-specific antibody binding sites. Sample OD was plotted against the standard curve to determine leptin content. The sensitivity of the assay is 0.4 ng/ml with a standard range of 0–500 ng/ml. Intra- and interassay variation is 7 and 10.2%, respectively. Urinary cortisol was determined using the Corte-Cote RIA (ICN Biomedicals, Inc., Aurora, OH). The sensitivity of the assay is 0.07 µg/dl. Intra- and interassay variation is 4.7 and 7.4%, respectively. Plasma norepinephrine was determined using HPLC with electrochemical detection (University of North Carolina General Clinical Research Center).

Statistical analysis

Average baseline values were calculated as the mean of min 15, 17, and 19. Ghrelin, leptin, cortisol, and norepinephrine data were log transformed before analysis. Group differences were determined using {chi}2 and ANOVA, correlations were computed using Pearson’s product moment, and linear regression was used to evaluate relationships between continuous variables. All analyses were carried out using SAS software (version 8.0, SAS Institute, Cary, NC). Results were expressed as the mean ± SD unless otherwise stated. P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Table 1Go depicts characteristics of the study population. Thirteen black women and six white women were obese [body mass index (BMI) >30 kg/m2]. Compared with white women, black women had higher BMI (32.6 ± 5.8 vs. 28.4 ± 5.8 kg/m2), waist circumference (109.4 ± 16.1 vs. 98.5 ± 19.0 cm), and waist-hip ratio (0.90 ± 0.07 vs. 0.86 ± 0.08). Black women also had higher resting systolic and diastolic BP (137.5/80.6 vs. 121.5/72.0 mm Hg) and leptin levels (56.1 ± 36.2 vs. 24.9 ± 24.8 ng/ml), compared with white women, and they tended to have higher systemic vascular resistance index (2851.8 ± 1078.8 vs. 2318.8 ± 600.8 dyne-sec/cm–5 x m2).


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  		TABLE 1. Characteristics of the study sample

 
Compared with their nonobese counterparts, obese women had lower SV index (47.1 ± 10.8 vs. 37.9 ± 14.9 ml/m2) and higher vascular resistance index (2350.5 ± 750.4 vs. 2869.6 ± 1007.9 dyne-sec x cm–5 x m2). Leptin was higher in obese women (22.4 ± 23.3 vs. 62.6 ± 33.3 ng/ml), and this effect was in large part due to obese black women, who had the highest average leptin level overall (Fig. 1Go, top).



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  		FIG. 1. Two-hour postprandial mean (± SE) leptin (top) and ghrelin (bottom) in obese and nonobese white and black women. Pair-wise least-squares mean comparisons vs. obese black group, *, P < 0.10; **, P < 0.05; ***, P < 0.001.

 
The ratio of pre- to postmenopausal women did not differ as a function of obesity or race ({chi}2 >0.66).

Race and obesity group differences in ghrelin

Effect of race. Ghrelin levels differed as a function of racial group: mean (± SD) ghrelin was higher in black, compared with white, women (0.33 ± 0.16 vs. 0.24 ± 0.12 ng/ml). As seen in Fig. 1Go (bottom), this racial group difference in ghrelin was in large part due to obese black women, who exhibited the highest average ghrelin level overall. However, the racial group difference in ghrelin remained significant after univariate adjustment for BMI, body weight, age, and leptin differences (P < 0.05), suggesting that race was not simply a proxy for BMI-related or caloric-intake-related differences in ghrelin.

Effect of obesity. Ghrelin did not differ significantly between obese and nonobese subjects (0.31 ± 0.17 vs. 0.27 ± 0.12 ng/ml, respectively), and, unexpectedly, ghrelin was not inversely related to general obesity (as indexed by BMI) in this sample of women. Instead, central obesity, as measured by waist-hip ratio, did show the expected inverse correlation with ghrelin in white women (r = –0.43, P < 0.04), but this relationship was not present in black women (r = –0.09, P > 0.67). Similar to what was observed for ghrelin and leptin levels, this lack of the typical relationship between ghrelin and waist-hip ratio was largely due to obese black women (Fig. 2Go).



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  		FIG. 2. Relationship between log-transformed postprandial ghrelin (x-axis) and waist-hip ratio (y-axis) in obese and nonobese black and white women. Ln, Lognormal.

 
Relationship of ghrelin to neuroendocrine and cardiovascular function: effect of race and obesity

As shown in Fig. 3Go, ghrelin was strongly and significantly correlated with 24-h urinary cortisol in black women (r = 0.61, P < 0.004) but not in white women (r = –0.21, P > 0.34). In multivariate regression analysis, a significant race X ghrelin interaction was detected for cortisol (ß = 1.53, P < 0.007), and this effect remained intact after adjusting for age, BMI, waist-hip ratio, and leptin levels and removing the influence of one obese white woman’s cortisol value that was deemed an outlier (P < 0.03). Ghrelin was also associated with higher resting heart rate in white women (r = 0.44, P < 0.04) but not black women (r = –0.09, P > 0.68), yielding a marginally significant race X ghrelin interaction term for heart rate (P = 0.10).



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  		FIG. 3. Relationship between log-transformed postprandial ghrelin (x-axis) and 24-h urinary cortisol (y-axis) in obese and nonobese black and white women. Ln, Lognormal.

 
When evaluated as a function of obesity, higher ghrelin was related to higher resting diastolic BP in obese (r = 0.55, P < 0.02) but not in nonobese women (r = –0.05, P > 0.83; Fig. 4Go). In contrast, higher ghrelin was associated with lower plasma norepinephrine in obese women (r = –0.63, P = 0.005) but not nonobese women (r = –0.22, P > 0.30). The relationships of ghrelin to diastolic BP and norepinephrine were essentially identical in both racial groups.



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  		FIG. 4. Relationship between log-transformed postprandial ghrelin (x-axis) and resting diastolic BP (y-axis) in black and white obese and nonobese women. Ln, Lognormal.

 
Summary

Independently, ghrelin was elevated in black women and leptin levels were elevated in obese women, and the subset of obese, black women exhibited the highest overall ghrelin and leptin levels. In addition, in this same subset of obese black women, ghrelin levels appeared to be independent of central obesity, whereas in white women, the expected inverse relationship between central obesity and ghrelin was obtained.

The relationships between ghrelin and cortisol and between ghrelin and heart rate likewise differed as a function of race. Higher ghrelin was associated with higher cortisol only in black women and higher resting heart rate only in white women. Higher ghrelin was linked to higher diastolic BP and lower norepinephrine in both black and white obese women.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Previously, plasma ghrelin concentrations have been shown to vary as a function of age and obesity. The present study, which compared ghrelin levels in a biracial sample of women, suggests that ghrelin also varies as a function of ethnicity. Plasma ghrelin concentrations measured 2 h after a standard test meal of mixed nutrient content were elevated in black, compared with white, women, and this effect was more pronounced in black women who were also obese. Contrary to previous reports, ghrelin concentration did not correlate inversely with BMI in the overall sample, and it was not significantly lower in obese, compared with nonobese, women. Rather, lower ghrelin was associated with greater central obesity (waist-hip ratio) in white women, but no such relationship existed in black women. Moreover, the absence of a ghrelin-obesity relationship was most evident in obese black women. Reasons for elevated ghrelin in black women are not clear but could be attributed to higher chronic (premeal) levels, lesser postprandial ghrelin suppression, or more rapid rebound of suppressed postprandial ghrelin levels.

Fasting ghrelin level is correlated with insulin resistance and inversely related to insulin level (9, 15, 34); controlling for insulin level or resistance negated the relationship between ghrelin and BMI (15). Higher insulin resistance has been observed in black, compared with white, women (35), and BMI and ghrelin were unrelated in the present study, particularly among obese black women, suggesting the possibility of a higher level of insulin resistance in that subgroup. Previous studies (36, 37) demonstrated a positive correlation between leptin and insulin resistance in women; thus, our finding of elevated leptin in black women, and particularly in obese black women, further supports the speculation of insulin resistance in that subgroup. Although not directly evaluated in the present study, insulin deficiency or insulin resistance may have accounted for the higher ghrelin level observed in black women. Future studies to elucidate racial differences in the connection between insulin resistance and ghrelin would be worthwhile.

Ghrelin is normally suppressed after meal intake, and this effect is at least in part dependent on insulin and obesity such that subnormal suppression of ghrelin might be anticipated in obese, insulin-resistant individuals (9, 13, 14, 38, 39) and type 2 diabetics (40). In addition, the return of ghrelin to premeal levels may be accelerated in obese individuals and diabetic patients (10). In the present study, ghrelin levels were measured 2 h after meal ingestion, a point at which ghrelin levels typically remain suppressed relative to premeal levels in healthy individuals but may already be rebounding in metabolically at-risk individuals (8, 10). Given the higher incidence of obesity and excess diabetes-related mortality in the larger population from which our sample was drawn (blacks living in the southeastern United States and in North Carolina in particular), it is not unreasonable to suspect that higher ghrelin levels observed in black women in this study were due, at least in part, to subnormal postprandial ghrelin suppression and/or accelerated ghrelin rebound.

It has been proposed that lesser postprandial ghrelin suppression and/or a more rapid postprandial ghrelin rebound may contribute to increased food intake in obesity (9) and hyperphagia that is common in insulin-deficient states (41, 42). Ghrelin promotes carbohydrate consumption and reduced fat depot use (43), and a high ghrelin level is associated with faster gastric emptying (8). According to a recent study (44), after a low- vs. high-caloric-load meal, ghrelin suppression is less dramatic, and the time to subsequent spontaneous request for more food is shorter. However, the findings did not support a definitive link between the extent of ghrelin suppression and time to spontaneous request for food. Given that all participants in the present study ate a controlled diet consisting of standard mixed-nutrient, fixed-calorie meals for 4 d and also 2 h before the measurement of ghrelin levels, it is unlikely that nonrandom differences in relative caloric load (or in macronutrient content) could explain the observations of higher ghrelin and higher leptin in black women. Because total caloric load was also adjusted for body size, it is also unlikely that ghrelin levels were higher in obese black women due to a systematic study-induced state of negative energy balance (11, 12).

Ghrelin administration induces the release of ACTH and cortisol (45). In the present study, ghrelin level correlated highly with 24-h urinary cortisol but only in black women. Elevated cortisol is a common finding in obesity (46, 47) and in patients with peripheral vascular disease (48) and diabetes mellitus, particularly those who are in poor control (49). Among women in particular, higher cortisol is independently associated with coronary stenosis (50), and adverse cardiovascular risk is greatest in those with the combination of obesity and failure to down-regulate cortisol levels (51). By self-report, all women in the present study had negative histories for coronary artery and peripheral vascular disease as well as diabetes, but it is not known whether black and white women differed in the incidence or severity of subclinical disease. Elevated cortisol in obesity, per se, is in large part due to hypothalamic dysregulation, particularly a disruption in the cortisol-ACTH feedback system (52). Peripheral ghrelin produced in the gastrointestinal tract stimulates GH release and regulates energy balance via its actions in the mediobasal and mediolateral hypothalamus (4, 5, 6). Ghrelin is also produced in hypothalamic neurons (5, 6). Thus, the elevations in ghrelin observed in black women and the strong ghrelin-cortisol relationship might reflect alterations in the control of ghrelin secretion (41, 42) and may be a precursor or marker of existing generalized hypothalamic dysregulation leading to subclinical disease in this group. Future angiographic studies could be instrumental in directly addressing this question.

Recent findings suggest that ghrelin exerts cardiovascular and hemodynamic effects, in part, via its actions on renal sympathetic nerve activity and vasopressin regulation (19, 20, 21). In healthy male subjects, acute ghrelin administration reduced mean arterial pressure and increased SV and cardiac index (18); and fasting plasma ghrelin was inversely associated with several indexes of right ventricular function (17). Our finding of higher heart rate associated with ghrelin in white women appears consistent with these findings, yet our data suggesting that higher ghrelin is associated with higher diastolic BP and lower plasma norepinephrine in obese women is not. Individual differences in response to the dietary sodium load during the 4 d before testing could contribute to these latter findings. Salt loading is associated with decreased urinary norepinephrine (53) and is linked to diastolic BP increases in persons who are salt sensitive, a trait that may be more common in obese individuals (54). The effects of salt loading on ghrelin have not been examined, but there are limited data suggesting a role of sodium-dependent channels in ghrelin’s stimulatory effect on intracellular calcium (55). Although the present study did not evaluate salt sensitivity, per se, it is reasonable to speculate a renal/sodium-mediated ghrelin-cardiovascular connection underlying the race and obesity differences in our data. Taken together, this collection of studies suggests a need for additional investigations of sodium load (along with potassium, calcium, and magnesium loads) on ghrelin and associated cardiovascular effects, and such studies should take into account the interactive effects of race, feeding state, and gender.

The strengths of the present study include the novel examination of race as a potential modifier of ghrelin, and the timing of metabolic and cardiovascular measurements after a rigidly timed postmeal ingestion protocol. In addition, whereas previous studies have focused on changes in fasting ghrelin after a single meal or ghrelin administration, the present study reflects a more naturalistic challenge that ensued after a 4-d controlled diet representative of local and regional dietary intake (56). Limitations of this study include the absence of insulin and insulin resistance measures and the absence of premeal and more frequent postmeal ghrelin assessments to better characterize interim ghrelin dynamics. Collection of such data in future studies will play an integral role in clarifying whether the current observations reflect ethnic differences in chronic ghrelin levels in immediate premeal levels, postprandial suppression and rebound, or some combination thereof.

In summary, in black women, independent of BMI, ghrelin was elevated and higher ghrelin was associated with higher cortisol. These findings were especially noteworthy in the subset of obese black women, who also exhibited significantly elevated leptin. Previously our research group demonstrated differences between blacks and whites in physiological responses that may contribute to increased cardiovascular risk. Prior observations include increased vascular resistance during stress, increased left ventricular wall thickness for the same level of blood pressure, decreased ß-receptor responsivity, and slowed sodium excretion during stress in blacks (57, 58, 59, 60). Blacks living in the southeastern United States, particularly in North Carolina in which this study was conducted, experience higher rates of overweight/obesity and suffer total mortality burdens from heart disease, diabetes, and stroke in excess of whites. The burden of premature death (before age 65 yr) due to heart disease is particularly high among black women (21.7%), compared with their white counterparts (7.7%). The link between ghrelin and cortisol and subsequently between cortisol and these disease states suggests that further investigation of the role of ghrelin in cardiovascular morbidity among black women is warranted.


   Footnotes
 
This work was supported by National Institutes of Health Grants R01 HL64927, R01 HL31533, K23 HL04223, and RR00046 to the General Clinical Research Centers at the University of North Carolina and Pennsylvania State University.

Abbreviations: BMI, Body mass index; BP, blood pressure; SV, stroke volume.

Received March 30, 2004.

Accepted June 8, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K 1999 Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402:656–660[CrossRef][Medline]
  2. De Ambrogi M, Volpe S, Tamanini C 2003 Ghrelin: central and peripheral effects of a novel peptydil hormone. Med Sci Monit 9:RA217–RA224
  3. Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Murphy KG, Dhillo WS, Ghatei MA, Bloom SR 2001 Ghrelin influences appetite and increases food intake in humans. J Clin Endocrinol Metab 86:5992–5995[Abstract/Free Full Text]
  4. Tschop M, Smiley D, Heiman M 2000 Ghrelin induces adiposity in rodents. Nature 407:908–913[CrossRef][Medline]
  5. Horvath TL, Diano S, Tschop M 2003 Ghrelin in hypothalamic regulation of energy balance. Curr Top Med Chem 3:921–927[CrossRef][Medline]
  6. Horvath TL, Diano S, Sotonyi P, Heiman M, Tschop M 2001 Minireview: ghrelin and the regulation of energy balance—a hypothalamic perspective. Endocrinology 142:4163–4169[Abstract/Free Full Text]
  7. Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE, Weigle DS 2001 A preprandial rise in plasma ghrelin level suggests a role in meal initiation in humans. Diabetes 50:1714–1719[Abstract/Free Full Text]
  8. Tschop M, Wawarta R, Riepl RL, Friedrich S, Midlingmaier M, Landfrat R, Folwaczny C 2001 Post-prandial decrease of circulating human ghrelin levels. J Endocrinol Invest 24:RC19–RC21
  9. Murdolo G, Lucide P, Di Loreto C, Parlanti M, De Cicco A, Fatone C, Fanelli CG, Bolli GB, Santeusanio F, De Feo P 2003 Insulin is required for prandial ghrelin suppression in humans. Diabetes 52:2923–2937[Abstract/Free Full Text]
  10. Shiiya T, Nakazato M, Mizuta M, Date Y, Mondal MS, Tanaka M, Nozoe S, Hosoda H, Kangawa K, Matsukura S 2002 Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion. J Clin Endocrinol Metab 87:240–244[Abstract/Free Full Text]
  11. Marzullo P, Verti B, Savia G, Walker GE, Guzzaloni G, Tagliaferri M, De Blasio A, Liuzzi A 2004 The relationship between active ghrelin levels and human obesity involves alterations in resting energy expenditure. J Clin Endocrinol Metab 89:936–939[Abstract/Free Full Text]
  12. Ravussin E, Tschop M, Morales S, Bouchard C, Heiman ML 2001 Plasma ghrelin concentration and energy balance: overfeeding and negative energy balance studies in twins. J Clin Endocrinol Metab 86:4547–4551[Abstract/Free Full Text]
  13. Greenman Y, Golani N, Gilad S, Yaron M, Limor R, Stern N 2004 Ghrelin secretion is modulated in a nutrient- and gender-specific manner. Clin Endocrinol (Oxf) 60:382–388[CrossRef][Medline]
  14. English PJ, Ghatei MA, Malik IA, Bloom SR, Wilding JP 2002 Food fails to suppress ghrelin levels in obese humans. J Clin Endocrinol Metab 87:2984–2987[Abstract/Free Full Text]
  15. Purnell JQ, Weigle DS, Breen P, Cummings DE 2003 Ghrelin levels correlate with insulin levels, insulin resistance, and high-density lipoprotein cholesterol, but not with gender, menopausal status, or cortisol levels in humans J Clin Endocrinol Metab 88:5747–5752
  16. Tschop M, Weyer C, Tataranni PA, Devanarayan V, Ravussin E, Heiman ML 2001 Circulating ghrelin levels are decreased in human obesity. Diabetes 50:707–709[Abstract/Free Full Text]
  17. Tritos NA, Kissinger KV, Manning WJ, Danias PG 2004 Association between ghrelin and cardiovascular indexes in healthy obese and lean men. Clin Endocrinol (Oxf) 60:60–66[CrossRef][Medline]
  18. Nagaya N, Kojima M, Uematsu M, Yamagishi M, Hosoda H, Oya H, Hayashi Y, Kangawa K 2001 Hemodynamic and hormonal effects of human ghrelin in healthy volunteers. Am J Physiol Regul Integr Comp Physiol 280:R1483–R1487
  19. Nagaya N, Miyatake K, Uematsu M, Oya H, Shimizu W, Hosoda H, Kojima M, Nakanishi N, Mori H, Kangawa K 2001 Hemodynamic, renal, and hormonal effects of ghrelin infusion in patients with chronic heart failure. J Clin Endocrinol Metab 86:5854–5859[Abstract/Free Full Text]
  20. Ishizaki S, Murase T, Sugimura Y, Kakiya S, Yokoi H, Tachikawa K, Arima H, Miura Y, Oiso Y 2002 Role of ghrelin in the regulation of vasopressin release in conscious rats. Endocrinology 143:1589–1593[Abstract/Free Full Text]
  21. Matsumura K, Tsuchihashi T, Fujii K, Age I, Iida M 2002 Central ghrelin modulates sympathetic activity in conscious rabbits. Hypertension 40:694–699[Abstract/Free Full Text]
  22. Mokdad AH, Marks JS, Stroup DF, Gerberding JL 2004 Actual causes of death in the United States, 2000. JAMA 291:1238–1245[Abstract/Free Full Text]
  23. Centers for Disease Control and Prevention 2004 Available at: http://www.cdc.gov/nccdphp/dnpa/obesity/trend/index.htm
  24. Hubert HB, Feinleib M, McNamara PM, Castelli WP 1983 Obesity as an independent risk factor for cardiovascular disease: a 26 year follow-up of participants in the Framingham Heart Study. Circulation 67:968–977[Abstract/Free Full Text]
  25. Rexrode KM, Manson JE, Hennekens CH 1996 Obesity and cardiovascular disease. Curr Opin Cardiol 11:490–495[CrossRef][Medline]
  26. Colditz GA, Willett WC, Rotnitzky A, Manson JE 1995 Weight gain as a risk factor for clinical diabetes mellitus in women. Ann Intern Med 122:481–486[Abstract/Free Full Text]
  27. Lundgren H, Bengtsson C, Blohme G, Lapidus L, Sjostrom L 1989 Adiposity and adipose tissue distribution in relation to incidence of diabetes in women: results from a prospective population study in Gothenburg, Sweden. Int J Obes 13:413–423[Medline]
  28. Winkleby MA, Kraemer HC, Ahn DK, Varady AN 1998 Ethnic and socioeconomic differences in cardiovascular disease risk factors: findings for women from the Third National Health and Nutrition Examination Survey, 1988–1994. JAMA 280:356–362[Abstract/Free Full Text]
  29. Girdler SS, Light KC 1994 Hemodynamic stress responses in men and women examined as a function of female menstrual cycle phase. Int J Psychophysiol 17:233–248[CrossRef][Medline]
  30. Sherwood A, Allen MT, Fahrenbert J, Kelsey RM, Lovalo WR, van Doornen LJ 1990 Methodological guidelines for impedance cardiography. Psychophysiology 27:1–23[Medline]
  31. Sherwood A, Girdler SS, Bragdon EE, West SG, Brownley KA, Hinderliter AL, Light KC 1997 Ten-year stability of cardiovascular responses to laboratory stressors. Psychophysiology 24:185–191
  32. Kubicek WG, Karnegis JN, Patterson RP, Witsoe DA, Mattson RH 1966 Development and evaluation of an impedance cardiac output system. Aerospace Med 37:1208–1212[Medline]
  33. Sherwood A, May CW, Siegel WC, Blumenthal JA 1995 Ethnic differences in hemodynamic responses to stress in hypertensive men and women. Am J Hypertens 8:552–557[CrossRef][Medline]
  34. Saad MF, Bernaba B, Hwu CM, Jinagouda S, Fahmi S, Kogosov E, Boyadjian R 2002 Insulin regulates plasma ghrelin concentration. J Clin Endocrinol Metab 87:3997–4000[Abstract/Free Full Text]
  35. Sowers M, Crawford SL, Cauley JA, Stein E 2003 Association of lipoprotein(a), insulin resistance, and reproductive hormones in a multiethnic cohort of pre- and perimenopausal women (the SWAN study). Am J Cardiol 92:533–537[CrossRef][Medline]
  36. Larsson H, Elmstahl S, Ahren B 1996 Plasma leptin levels correlate to islet function independently of body fat in postmenopausal women. Diabetes 45:1580–1584[Abstract]
  37. Ahren B, Larsson H 1997 Leptin—a regulator of islet function? Its plasma levels correlate with glucagon and insulin secretion in healthy women. Metabolism 46:1477–1481[CrossRef][Medline]
  38. Lucidi P, Murdolo G, Di Loreto C, De Cicco A, Parlanti N, Fanelli C, Santeusanio F, Bolli GB, De Feo P 2002 Ghrelin is not necessary for adequate hormonal counter-regulation of insulin-induced hypoglycemia. Diabetes 51:2911–2914[Abstract/Free Full Text]
  39. Morpugo PS, Resnik M, Agosti F, Cappiello V, Sartorio A, Spada A 2003 Ghrelin secretion in severely obese subjects before and after a 3-week integrated body mass reduction program. J Endocrinol Invest 26:723–727[Medline]
  40. Anderwald C, Brabant G, Bernroider E, Horn R, Brehm A, Waldhausl W, Roden M 2003 Insulin-dependent modulation of plasma ghrelin and leptin concentrations is less pronounced in type 2 diabetic patients. Diabetes 52:1792–1798[Abstract/Free Full Text]
  41. Ishii S, Kamegai J, Tamura H, Shimizu T, Sugihara H, Oikawa S 2002 Role of ghrelin in streptozotocin-induced diabetic hyperphagia. Endocrinology 143:4934–4937[Abstract]
  42. Masaoka T, Suzuki H, Hosoda H, Ota T, Minegishi Y, Nagata H, Kangawa K, Ishii H 2003 Enhanced plasma ghrelin levels in rats with streptozotocin-induced diabetes. FEBS Lett 541:64–68[CrossRef][Medline]
  43. Casanueva FF, Dieguez C 2002 Ghrelin: the link connecting growth with metabolism and energy homeostasis. Rev Endocrinol Metab Disord 3:325–338
  44. Callahan HS, Cummings DE, Pepe MS, Breen PA, Matthys CC, Weigle DS 2004 Postprandial suppression of plasma ghrelin level is proportional to ingested caloric load but does not predict intermeal interval in humans. J Clin Endocrinol Metab 89:1319–1324[Abstract/Free Full Text]
  45. Arvat E, Maccario M, Di Vito L, Broglio F, Benso A, Gottero C, Papotti M, Muccioli G, Dieguez C, Casanueva FF, Deghenghi R, Camanni F, Ghigo E 2002 Endocrine activities of ghrelin, a natural growth hormone secretagogue (GHS), in humans: comparison and interactions with hexarelin, a nonnatural peptidul GHS, and GH-releasing hormone. J Clin Endocrinol Metab 86:1169–1174
  46. Douyon L, Schteingart DE 2002 Effect of obesity and starvation on thyroid hormone, growth hormone, and cortisol secretion. Endocrinol Metab Clin North Am 31:173–189[CrossRef][Medline]
  47. Bjorntorp P, Rosmond R 2000 Obesity and cortisol. Nutrition 16:924–936[CrossRef][Medline]
  48. Stancakova A, Merstenova E, Vajo J, Valkova M 1978 The excretion of free cortisol, cortisone, cortisol sulfate and cortisone sulfate in peripheral vascular disease, diabetes mellitus and hyperthyroidism. Horm Metab Res 10:539–544[Medline]
  49. Couch RM 1992 Dissociation of cortisol and adrenal androgen secretion in poorly controlled insulin-dependent diabetes mellitus. Acta Endocrinol (Copenh) 127:115–117[Abstract/Free Full Text]
  50. Koertge J, Al-Khalili F, Ahnve S, Janszky I, Svane B, Schenck-Gustafsson K 2002 Cortisol and vital exhaustion in relation to significant coronary artery stenosis in middle-aged women with acute coronary syndrome. Psychoneuroendocrinology 27:893–906[CrossRef][Medline]
  51. Walker BR, Soderberg S, Lindahl B, Olsson T 2000 Independent effects of obesity and cortisol in predicting cardiovascular risk factors in men and women. J Intern Med 247:198–204[CrossRef][Medline]
  52. Strain GW, Zumoff B, Kream J, Strain JJ, Levin J, Fukushima D 1982 Sex difference in the influence of obesity on the 24 hr mean plasma concentration of cortisol. Metabolism 31:209–212[CrossRef][Medline]
  53. Foo M, Denver AE, Coppack SW, Yudkin JS 1998 Effect of salt-loading on blood pressure, insulin sensitivity and limb blood flow in normal subjects. Clin Sci (Lond) 95:157–164[Medline]
  54. Dimsdale JE, Ziegler M, Mills P, Berry C 1990 Prediction of salt sensitivity. Am J Hypertens 3:429–435[Medline]
  55. Glavaski-Joksimovic A, Jeftinija K, Scanes CG, Anderson LL, Jeftinija S 2003 Stimulatory effect of ghrelin on isolated porcine somatotropes. Neuroendocrinology 77:367–379[CrossRef][Medline]
  56. Gerber AM, James SA, Ammerman AS, Keenan NL, Garrett JM, Strogatz DS, Haines PS 1991 Socioeconomic status and electrolyte intake in black adults: the Pitt County study. Am J Public Health 81:1608–1612[Abstract/Free Full Text]
  57. Light KC, Turner JR 1992 Stress-induced changes in the rate of sodium excretion in healthy black and white men. J Psychosom Res 36:497–508[CrossRef][Medline]
  58. Light KC, Turner JR, Hinderliter AL, Sherwood A 1993 Race and gender comparisons: I. Hemodynamic responses to a series of stressors. Health Psychol 12:354–365[CrossRef][Medline]
  59. Hinderliter AL, Blumenthal JA, Waugh R, Chilukuri M, Sherwood A 2004 Ethnic differences in left ventricular structure: relations to hemodynamics and diurnal blood pressure variation. Am J Hypertens 17:43–49[CrossRef][Medline]
  60. Sherwood A, Hinderliter AL 1993 Responsiveness to {alpha}- and ß-adrenergic receptor agonists: effects of race in borderline hypertensive compared with normotensive men. Am J Hypertens 6:630–635[Medline]



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F. Bacha and S. A. Arslanian
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