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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2008-0207
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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 8 3149-3157
Copyright © 2008 by The Endocrine Society

Circulating Ghrelin, Leptin, and Soluble Leptin Receptor Concentrations and Cardiometabolic Risk Factors in a Community-Based Sample

Erik Ingelsson, Martin G. Larson, Xiaoyan Yin, Thomas J. Wang, James B. Meigs, Izabella Lipinska, Emelia J. Benjamin, John F. Keaney, Jr. and Ramachandran S. Vasan

The Framingham Study (E.I., M.G.L., X.Y., T.J.W., E.J.B., R.S.V.), Boston University School of Medicine, Framingham, Massachusetts 01702-5803; Department of Medical Epidemiology and Biostatistics (E.I.), Karolinska Institutet, SE-171 77 Stockholm, Sweden; Department of Mathematics and Statistics (M.G.L.), Boston University, and Evans Memorial Department of Medicine and Whitaker Cardiovascular Institute (I.L., E.J.B., R.S.V.), Boston University School of Medicine, Boston, Massachusetts 02215; Department of Biostatistics (X.Y.), Boston University School of Public Health, Boston, Massachusetts 02118; Massachusetts General Hospital and Harvard Medical School (T.J.W.) and Department of Medicine (J.B.M.), Massachusetts General Hospital, Boston, Massachusetts 02114; and Division of Cardiovascular Medicine (J.F.K.), University of Massachusetts Medical School, Worcester, Massachusetts 01655

Address all correspondence and requests for reprints to: Ramachandran S. Vasan, M.D., F.A.C.C., Framingham Heart Study, 73 Mount Wayte Avenue, Suite 2, Framingham, Massachusetts 01702-5803. E-mail: vasan{at}bu.edu.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: The conjoint effects and relative importance of ghrelin, leptin, and soluble leptin receptor (sOB-R), adipokines involved in appetite control and energy expenditure in mediating cardiometabolic risk, is unknown.

Objective: The objective of the study was to study the cross-sectional relations of these adipokines to cardiometabolic risk factors in a community-based sample.

Design, Setting, and Participants: We measured circulating ghrelin, leptin, and sOB-R in 362 participants (mean age 45 yr; 54% women) of the Framingham Third Generation Cohort.

Main Outcome Measures: Body mass index, waist circumference (WC), blood pressure, lipid measures, fasting glucose, smoking, and metabolic syndrome (MetS) were measured.

Results: Ghrelin and leptin concentrations were significantly higher in women (P < 0.0001). In multivariable models, ghrelin was inversely associated with age and systolic blood pressure, and leptin was positively related to body mass index and WC. sOB-R was positively associated with age, total cholesterol, and fasting glucose and inversely with WC and high-density lipoprotein cholesterol. Ghrelin and sOB-R concentrations were significantly lower with number of MetS components (P for trend = 0.022 and < 0.0001, respectively), whereas leptin concentrations were higher (P for trend = 0.0001). Relating all adipokines to MetS conjointly, higher ghrelin and leptin concentrations were associated with decreased and increased odds of MetS (odds ratio 0.55, P < 0.0001; odds ratio 4.44, P = 0.0002, per 1 SD increase of respective log adipokine).

Conclusions: In our community-based sample, we observed a sexual dimorphism in circulating ghrelin and leptin concentrations. Ghrelin, leptin, and sOB-R were associated with number of MetS components cross-sectionally, consistent with the hypothesis that these adipokines may have a central role in cardiometabolic risk.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
Recent research has highlighted the role of gut hormones and other neuroendocrine hormones that control appetite and energy expenditure in the development of obesity, insulin resistance, and other cardiometabolic risk factors (1, 2). These hormones include leptin, ghrelin, peptide YY, cholecystokinin, and glucagon-like peptide 1, among others.

Ghrelin was first described as the endogenous ligand for a new GH secretagogue receptor (3). Additional research has elucidated that it is a powerful inducer of GH release and functions as an appetite-stimulating signal from the gut to the brain (4). It counters the anorexigenic effect of leptin and is an important coordinator of behavioral, metabolic, and gastrointestinal responses to fasting and eating. Low concentrations of circulating ghrelin have been associated with obesity, insulin resistance, and type 2 diabetes (5, 6, 7, 8, 9).

Leptin acts as a satiety signal, regulates appetite and energy expenditure, but has also a range of other physiological functions including regulation of puberty, placental function, peripheral insulin sensitivity, and interaction with other hormonal mediators and regulators (10). Leptin binds to its receptor, the leptin receptor. In addition to several membrane-bound isoforms, a soluble form of the leptin receptor (sOB-R) is generated by cleavage of the membrane-bound forms (11). sOB-R has been proposed to function as a binding protein and is therefore an important regulator of leptin activity (10, 12). One way of characterizing the balance between leptin and sOB-R is the free leptin index (FLI), which is determined by calculating the ratio between the concentrations of leptin and sOB-R (13). Elevated concentrations of circulating leptin repeatedly have been associated with cardiometabolic risk factors, such as hypertension, obesity, insulin resistance, and type 2 diabetes (14, 15, 16, 17, 18, 19, 20, 21), whereas data regarding the correlations of sOB-R and FLI with cardiometabolic risk factors are more limited (22, 23, 24).

Whereas some prior studies have evaluated these biomarkers individually, to our knowledge none has assessed their conjoint effects and relative importance in mediating cardiometabolic risk. The balance between these important adipokines that regulate appetite control and energy expenditure may determine such risk. Accordingly, the aims of our study were to test the hypothesis that abnormal circulating concentrations of ghrelin, leptin, sOB-R, and FLI are associated (individually and conjointly) with adverse levels of cardiometabolic risk factors in a community-based sample.


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

The Framingham Third Generation Cohort was recruited between 2002 and 2005. The design and selection criteria for this cohort have been described elsewhere (25). Briefly, 4095 adults (53% women; mean age 40 yr) who have at least one parent in the Framingham Offspring Study cohort were enrolled. At their first examination, participants underwent anthropometry, medical history, physical examination, and laboratory assessment of cardiovascular risk factors. Smoking was ascertained by self-reported cigarette use during the year preceding the examination. The study was approved by the Institutional Review Board at Boston University Medical Center, and all participants provided written informed consent.

The present study was performed in a subsample of 362 participants (54% women) in whom ghrelin, leptin, and sOB-R were assayed. We randomly selected these participants using a weighted sampling scheme with oversampling of the lowest and highest sex-specific quintiles of body mass index (BMI; ratio of 1.5:2:1.5 for the lowest, middle three, and upper quintiles). We chose this sampling strategy for cost efficiency and optimizing use of nonrenewable serological resources, given the novelty of the biomarkers evaluated.

Laboratory measurements and definition of metabolic syndrome

Serum and plasma were drawn after an overnight fast and stored at –80 C until assay without previous thawing. Ghrelin was assayed using a commercially available ELISA kit (Phoenix Pharmaceuticals Inc., Belmont, CA) in unextracted serum, and leptin and sOB-R were assayed using a commercially available ELISA kit (R&D Systems Inc., Minneapolis, MN) in EDTA plasma. The average intraassay coefficients of variation were: ghrelin, 2.3%; leptin, 2.1%; and sOB-R, 3.1%.

The metabolic syndrome (MetS) was defined according to the modified National Cholesterol Education Program Adult Treatment Panel III criteria (26), by the presence of three or more of the following: increased waist circumference [≥88 (women) or ≥102 cm (men)]; elevated blood pressure (≥130 mm Hg systolic or ≥85 mm Hg diastolic or treatment for hypertension); hyperglycemia [fasting blood glucose ≥100 mg/dl (5.6 mmol/liter) or treatment for elevated glucose]; hypertriglyceridemia [serum concentration ≥150 mg/dl (1.7 mmol/liter)]; or low high-density lipoprotein (HDL) cholesterol [<50 mg/dl (1.3 mmol/liter, women) or <40 mg/dl (1.03 mmol/liter, men)].

Statistical methods

Ghrelin, leptin, sOB-R, and FLI concentrations were logarithmically transformed to normalize their skewed distributions. Age- and sex-adjusted Spearman partial correlation coefficients were estimated for the pairwise correlations of the adipokines with each other and for the relations of the adipokines to cardiometabolic risk factors (27). We performed stepwise multivariable regressions with all cardiometabolic risk factors as the independent and the adipokines as the dependent variables to evaluate the clinical correlates of the adipokines. Age and sex were forced into these models, whereas P < 0.10 was used as the level for retention in the models for the other variables.

Age- and sex-adjusted least square means with 95% confidence intervals (CIs) of the adipokines were calculated stratifying by BMI category (normal, <25.0 kg/m2; overweight, 25.0 to <30.0 kg/m2; obesity, ≥30.0 kg/m2) and according to the number of MetS components present using logarithmically transformed biomarker concentrations. The values were then transformed back to original units to allow meaningful interpretation. Age-adjusted least square means of the adipokines in pre- and postmenopausal women were also estimated and compared.

Ghrelin, leptin, and sOB-R were related conjointly to MetS in an age- and sex-adjusted logistic regression model with MetS as the response variable and the log adipokines as the predictor variables. We examined effect modification by testing the statistical significance of the following first-order interaction terms in the multivariable models separately for each adipokine as dependent variables: BMI by sex, waist circumference by sex. Two-tailed 95% CIs and P values were estimated, with P < 0.05 considered statistically significant. Analyses were performed using SAS 9.1 (SAS Institute, Cary, NC).


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The characteristics of our study sample are shown in Table 1Go. The age- and sex-adjusted pairwise correlation was inverse between leptin and sOB-R (r = –0.43, P < 0.0001). Ghrelin was not significantly correlated with the other adipokines in our sample.


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  		TABLE 1. Characteristics of the study sample1

 
Ghrelin demonstrated inverse correlations with age, systolic, and diastolic blood pressure (Table 2Go). Leptin and FLI demonstrated significant positive correlations with all cardiometabolic risk factors but were inversely related to HDL cholesterol concentrations. sOB-R concentrations were inversely correlated with BMI, waist circumference, systolic and diastolic blood pressure, triglycerides, and fasting glucose and positively with HDL cholesterol. Smoking was not significantly correlated with any of the examined adipokines. The age- and sex-adjusted concentrations of ghrelin and sOB-R decreased, whereas leptin concentrations and FLI increased significantly across BMI categories (Fig. 1Go).


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  		TABLE 2. Correlations of ghrelin, leptin, sOB-R, and FLI and cardiometabolic risk factors1

 

Figure 1
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  		FIG. 1. Age- and sex-adjusted least square means of concentrations of ghrelin, leptin, sOB-R, and FLI in individuals with normal BMI (<25.0 kg/m2), overweight (BMI 25.0 to <30.0 kg/m2), and obesity (BMI ≥30.0 kg/m2).

 
In multivariable models examining the clinical correlates of adipokine concentrations, all adipokines were strongly correlated with sex (P ≤ 0.0009; Table 3Go). Concentrations of ghrelin, leptin, and FLI were higher in women, whereas sOB-R was lower. The age-adjusted means in premenopausal and postmenopausal women differed significantly for ghrelin (2.8 vs. 3.7 ng/ml, respectively; P = 0.024) but not for the other adipokines (leptin, 10.9 vs. 15.8 ng/ml; P = 0.10; sOB-R, 38.1 vs. 36.2 ng/ml; P = 0.47; and FLI, 0.29 vs. 0.44; P = 0.10).


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  		TABLE 3. Clinical correlates of ghrelin, leptin, sOB-R, and FLI1

 
In the multivariable models, age, sex, and systolic blood pressure were significantly associated with ghrelin concentrations (Table 3Go). The strongest correlate in this multivariable model was sex (partial R2 = 0.04). Sex, BMI, and waist circumference were significantly associated with leptin concentrations, whereas total cholesterol and triglycerides were retained as borderline significant correlates. The strongest correlate was BMI (partial R2 = 0.48). The significant correlates of sOB-R concentrations were age, sex, waist circumference, HDL cholesterol, and fasting glucose, whereas FLI concentrations were determined by age, sex, BMI, waist circumference, triglycerides, and fasting glucose. HDL cholesterol was retained as a borderline significant correlate in this multivariable model. The strongest correlate with sOB-R was waist circumference (partial R2 = 0.043) and the strongest with FLI was BMI (partial R2 = 0.50).

All adipokines were significantly associated with the number of components of MetS (Fig. 2Go). Ghrelin and sOB-R demonstrated decreasing concentrations with increase in the number of MetS components, whereas leptin concentrations and FLI increased. The age- and sex-adjusted least square means by presence vs. absence of obesity, and/or MetS are shown in Fig. 3Go. Ghrelin concentrations were lower in individuals with MetS, independently of obesity, whereas leptin, sOB-R and FLI concentrations differed across categories of obesity and MetS status in a linear fashion.


Figure 2
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  		FIG. 2. Age- and sex-adjusted least square means of concentrations of ghrelin, leptin, sOB-R, and FLI according to the number of components of the MetS. The numbers of participants per group were 111, 80, 79, 53, 26, and 13 (for none, one, two, three, four, and five components of MetS).

 

Figure 3
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  		FIG. 3. Age- and sex-adjusted least square means of concentrations of ghrelin, leptin, sOB-R, and FLI in nonobese individuals without MetS (Ob–/MetS–), nonobese individuals with MetS (Ob–/MetS+), obese individuals without MetS (Ob+/MetS–), and obese individuals with MetS (Ob+/MetS+).

 
When relating ghrelin, leptin, and sOB-R conjointly to MetS in age- and sex-adjusted analyses, higher ghrelin concentrations were associated with a decreased, and higher leptin concentrations were associated with an increased odds of MetS (Table 4Go). sOB-R was not significantly associated with MetS when modeled with ghrelin and leptin. In a multivariable model without leptin, log sOB-R [odds ratio (OR), 0.51; 95% CI 0.39–0.68; P < 0.0001 for a 1 SD increase] was associated with a decreased odds of MetS. Log ghrelin remained inversely related to MetS in this model (OR 0.57; 95% CI 0.43–0.76; P = 0.0001 for a 1 SD increase).


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  		TABLE 4. Conjoint consideration of the ghrelin, leptin, and sOB-R in relation to MetS1

 
None of the interaction terms was statistically significant (all P > 0.10). With our sample size, we had 80% power to detect an increment to the model R2 of 0.021 and to observe a partial correlation coefficient of 0.15 or greater (at {alpha} = 0.05).


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

In this study, we comprehensively characterized the cross-sectional relations of ghrelin, leptin, sOB-R concentrations, and the FLI with cardiometabolic risk factors in a community-based sample. Several interesting observations should be noted. First, we observed higher ghrelin, leptin, and FLI in women, whereas sOB-R concentrations were lower (in multivariable models simultaneously adjusting for other correlates), consistent with prior studies (28, 29, 30, 31, 32). The reasons for this sexual dimorphism are unknown but may include sex steroid effects, differential body fat distribution resulting in different secretion patterns of these adipokines, or other unknown factors. Second, the concentrations of all examined adipokines were associated with MetS, indicating that they may have a central role in mediating obesity, insulin resistance, and cardiovascular risk. Interestingly, presence or absence of MetS influenced adipokine concentrations independently of degree of obesity. This supports the notion of heterogeneity of risk by metabolic status among obese individuals (33). Third, ghrelin concentrations were not significantly correlated with leptin, sOB-R or FLI and demonstrated weaker associations with most of the cardiometabolic risk factors than the other biomarkers. Also, the model R2 in the multivariable model of clinical correlates of ghrelin concentrations was low, indicating that there may be other important factors determining ghrelin concentrations than those examined in the present study. Yet ghrelin was associated with MetS, even after adjustment for leptin and sOB-R. This could have been driven by a strong association with blood pressure and slight, but nonsignificant, associations with some of the other components of MetS. In contrast, leptin concentrations and FLI demonstrated a very high correlation, and they shared the same clinical correlates to a large degree. Also, sOB-R was correlated with similar cardiometabolic risk factors as leptin, although we observed some differences in their clinical correlates, a finding that would be interesting to pursue in a longitudinal study. However, when relating ghrelin, leptin, and sOB-R to MetS in a conjoint model, sOB-R was not significantly associated with MetS, presumably due to its high correlation with leptin.

Relations between ghrelin concentrations and cardiometabolic risk factors

In our study, ghrelin concentrations were inversely associated with blood pressure but not related to other cardiometabolic risk factors examined. Inverse relations between systolic and diastolic blood pressure and ghrelin have been previously reported in a case-control study of hypertensives and matched controls from the community (8). Furthermore, injection of ghrelin in healthy humans has been shown to decrease mean arterial pressure and increase cardiac output (34), and there is support for a vasodilating action of ghrelin, possibly through direct effects on the GH secretagogue receptor (also called ghrelin receptor) in the myocardium and aorta (34, 35).

Ghrelin is a stimulator of GH release, which in turn has been proposed to be related to myocardial growth and improved cardiac function. In addition to these GH-dependent actions, a direct effect of ghrelin on the cardiovascular system has been proposed because mRNA for both the peptide and its receptor have been detected in the heart (36). Taken together, these observations are consistent with a role for ghrelin in the regulation of blood pressure and vasomotor function.

Furthermore, mean ghrelin concentrations were significantly lower with increasing number of MetS components and across categories of increasing BMI in our study. These findings are consistent with prior studies that have reported lower concentrations of ghrelin in individuals with MetS (7, 9), insulin resistance (6), and obesity (5, 6). Meal-related ghrelin and insulin concentrations are reciprocal, and it has been suggested that ghrelin concentrations may be secondary to changes in glucose and insulin (37). Conversely, ghrelin deficiency could theoretically promote insulin resistance by different mechanisms including somatotrophic effects (38) and modulation of insulin signaling in peripheral tissues (39). The complex relations between ghrelin, insulin, and associated pathways are still largely unknown and merits further study.

Leptin, leptin receptor, and cardiometabolic risk factors

In our investigation, leptin concentrations were positively correlated with all of the examined correlates, except for smoking. Also, the concentrations increased with the number of MetS components present. These findings concur with prior studies that demonstrated that higher leptin concentrations are associated with elevated blood pressure (14), type 2 diabetes (15), obesity (16, 17), insulin resistance (17, 18), and the MetS (19, 20, 21). A recent study in midlife women demonstrated that increases of leptin over the menopause transition period were associated with decreases in HDL cholesterol and increases in diastolic blood pressure, glucose, and insulin resistance, whereas increases in ghrelin concentrations over the same period were associated with an increase of low-density lipoprotein cholesterol (40). In another longitudinal study, both leptin and ghrelin were associated with most of the MetS components at baseline, but they did not seem to mediate the relations of MetS with coronary heart disease mortality (41).

The adipocyte-derived hormone leptin functions as a satiety signal, reduces the appetite and increases the metabolism (10, 42). However, obese individuals have unusually high circulating concentrations of leptin, and the failure of leptin to suppress eating and promote weight loss in common forms of obesity have been termed leptin resistance (42). There is evidence that the association of leptin with insulin resistance may be independent of fat mass (17, 20), and hyperleptinemia has even been proposed as a component of the MetS (20). The exact mechanisms behind the relations of leptin and insulin resistance and the complex interactions with other cardiometabolic risk factors are not entirely known. Leptin functions as a growth factor in a range of cell types as a mediator of energy expenditure and by interaction with other hormonal mediators and regulators of energy status and metabolism such as insulin, glucagon, IGFs, GH, and glucocorticoids (10).

Data on the associations between sOB-R and cardiometabolic risk factors are sparse and confined to selective study samples. One previous smaller study in overweight or obese men noted that lower sOB-R concentrations were associated with insulin resistance, abdominal obesity, and MetS (22), whereas sOB-R concentrations were not significantly correlated with insulin or glucose in a smaller study of women with polycystic ovary syndrome (23). A study in healthy Greek adolescents showed that sOB-R correlated inversely with body fat mass (24). It is plausible that the mechanisms by which sOB-R is associated with clinical correlates are shared with leptin because sOB-R is the main leptin-binding molecule in plasma (43) and thus an important modulator of leptin action.

Strengths and limitations

The strengths of our study include the community-based sample and the comprehensive assessment of cardiometabolic risk factors in relation to three different adipokines individually and conjointly. There were several limitations of our study. We had limited statistical power to detect modest associations because our study was based on a subsample (9%) of the whole cohort and had a low prevalence of diabetes (5%). Second, we did not relate the adipokines to measures of insulin sensitivity/secretion. Third, our sample consisted of middle-aged, white individuals of European decent, limiting the generalizability of our findings to other age groups and ethnicities. Fourth, because our study was cross-sectional, we cannot assess causality or determine whether adipokine concentrations are related to longitudinal tracking of cardiometabolic risk factors. Fifth, ghrelin was measured in serum in the present study, and although this has been done in some prior reports (7, 41, 44, 45), it would have been preferable to use plasma and incorporate steps with addition of acid and protease inhibitors because ghrelin is known to be easily desacylated and/or degradated. However, a prior study demonstrated ghrelin concentrations in serum and four different plasma samples were very similar when samples were stored under optimal conditions (46).

Conclusions

In our community-based sample, ghrelin, leptin, sOB-R, and FLI demonstrated a sexual dimorphism, suggesting that appetite and energy expenditure control could be different in men and women. Furthermore, all examined adipokines were associated with the number of MetS components present. This finding is consistent with the hypothesis that these important regulators of appetite control and energy expenditure may have a central role in mediating cardiometabolic risk.


   Footnotes
 
This work was supported by the Swedish Heart-Lung Foundation and the Swedish Society of Medicine (to E.I.), and the National Heart, Lung, and Blood Institute’s Framingham Heart Study (Contract N01-HC-25195) and Grants K23-HL-074077 (to T.J.W.), RO1-HL-076784, 1R01 AG028321 (to E.J.B.), and 1RO1 DK 080739 and 2K24HL4334 (to R.S.V.). J.B.M. was supported by a Career Development Award from the American Diabetes Association and National Institute of Diabetes and Digestive and Kidney Diseases Grant K24 DK080140. The funding sources had no role in the study design, analyses, or drafting of the manuscript.

Disclosure Statement: The authors have nothing to disclose.

First Published Online May 20, 2008

Abbreviations: BMI, Body mass index; CI, confidence interval; FLI, free leptin index; HDL, high-density lipoprotein; MetS, metabolic syndrome; OR, odds ratio; sOB-R, soluble leptin receptor.

Received January 28, 2008.

Accepted May 14, 2008.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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