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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 6 2678-2683
Copyright © 2004 by The Endocrine Society

Obesity: Original Article

Serum Haptoglobin: A Novel Marker of Adiposity in Humans

C. Chiellini, F. Santini, A. Marsili, P. Berti, A. Bertacca, C. Pelosini, G. Scartabelli, E. Pardini, J. López-Soriano, R. Centoni, A. M. Ciccarone, L. Benzi, P. Vitti, S. Del Prato, A. Pinchera and M. Maffei

Dulbecco Telethon Institute (C.C., P.B., J.L-S., M.M.) and Department of Endocrinology and Metabolism, Sections of Endocrinology (F.S., A.M., C.P., G.S., R.C., P.V., A.P., C.C., P.B., J.L.-S., M.M.) and Metabolism (A.B., A.M.C., L.B., S.D.P.), University of Pisa, 56126 Pisa, Italy; and Azienda Ospedaliera Pisana (E.P.), 56126 Pisa, Italy

Address all correspondence and requests for reprints to: Dr. Margherita Maffei, Dulbecco Telethon Institute, Department of Endocrinology and Metabolism, Ospedale di Cisanello, Via Paradisa, 2, 56126 Pisa, Italy. E-mail: mmaffei{at}dti.telethon.it.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Haptoglobin (Hp) is a glycoprotein involved in the acute phase response to inflammation. Our previous findings indicate that Hp mRNA and protein are present in the adipose tissue of rodents and that Hp gene expression is up-regulated in obese models. The aim of the present study was to establish whether Hp could be considered a marker of obesity in humans. In 312 subjects, serum Hp was correlated directly with body mass index (BMI), leptin, C-reactive protein (CRP), and age. In a multivariate stepwise regression analysis, BMI and CRP were independent determinants of serum Hp in females, with BMI having the strongest effect. CRP and age were independent determinants of serum Hp in males, although explaining only a modest percentage of the total variability. Serum Hp was positively associated with body fat, as assessed by dual-energy x-ray absorptiometry, both in female and in male groups. The level of significance improved when serum Hp was analyzed against fat mass adjusted for lean mass. Finally, Northern and Western blot analyses performed in biopsies of sc abdominal fat from 20 obese individuals showed the presence of Hp mRNA and protein in the human adipose tissue.

In conclusion, serum Hp constitutes a novel marker of adiposity in humans, and the adipose tissue likely contributes to determine its levels.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
IN RECENT YEARS, an intriguing theory has looked at obesity as a low-grade systemic inflammation condition (1). This view is supported by several lines of evidence, including the association of obesity with elevated serum levels of C-reactive protein (CRP) (2), IL-6 (3), TNF-{alpha} (4), and leptin (5). Similarly, the acute phase reactant Pentraxin 3, a member of the pentraxin family closely related to CRP, has been found to be up-regulated in the white adipose tissue (WAT) of different models of murine obesity (6). The adipose tissue, until recently considered a passive depot of triglycerides, is emerging as an important endocrine organ (7) and the source for most of the above-mentioned factors also known as adipokines.

Along this line of findings, we recently reported that haptoglobin (Hp), a plasma glycoprotein involved in the hepatic acute phase response to inflammation (8), is present in murine WAT, as described previously by Friedrichs et al. (9), and that its gene expression is dramatically increased in genetically or experimentally induced obese mice (10).

We also identified TNF-{alpha} as an important signal for the observed obesity-dependent up-regulation. As a matter of fact, obese mice deficient for TNF-{alpha} or TNF-{alpha} receptors do not exhibit the typical increase of Hp mRNA observed in the obese controls (10). Moreover, in a recent study (11), the effect of a number of proinflammatory molecules on Hp expression was assessed in 3T3-L1 adipocytes, and TNF-{alpha} turned out as the strongest inducer. Within the clinical setting, plasma Hp is a marker of inflammation, its levels increasing significantly during inflammation, infection, and malignancy (9, 12).

The aim of the present study was to establish whether Hp can be considered a marker of obesity in humans. Therefore, Hp serum levels were measured in a cohort of lean and overweight/obese subjects and related with several clinical and metabolic parameters.


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

Three hundred twelve (221 females and 91 males) subjects referring to our Endocrinology and Metabolism Department were recruited consecutively over a 6-month period. Subjects with hypothyroidism or hyperthyroidism, overt diabetes, adrenal insufficiency or hypercortisolism, and infectious or malignant disorders were excluded from the study. Body mass index (BMI) and age range were 17.6–57.9 kg/m2 and 18–71 yr, respectively. Subcutaneous adipose tissue biopsies were obtained from 20 subjects (10 females and 10 males; BMI range, 20.5–45.2 kg/m2) at the time of elective open abdominal surgery. For this recruitment, we applied the same exclusion criteria mentioned above. The study protocol was approved by the local Ethical Committee (protocol no. 12327), and patients gave informed consent for their participation in the study.

Laboratory analysis

Blood samples were obtained by venipuncture after an overnight fasting, and samples were stored at –20 C until further analysis. Insulin was assayed by immunoradiometric assay (Medgenics Diagnostics, Fleurus, Belgium), with intraassay and interassay coefficients of variation (CV) of 4.5 and 10.2%, respectively. Plasma leptin concentration was measured by a RIA kit (catalog no. HL-81K; Linco Research, St. Charles, MO) using a polyclonal antibody raised in rabbits against recombinant leptin; the interassay CV was 5–7%. Hp serum concentration was measured by nephelometry (Dade-Behring, Marburg, Germany), with intraassay and interassay CV of 2.6 and 6.2%, respectively. CRP serum concentration was measured by nephelometry (Dade-Behring), and the intraassay and interassay CV were 2.4 and 4.4%, respectively. Plasma glucose was measured on fluorinated plasma samples (Gluco-quant, Roche/Hitachi modular analyzer; Roche Diagnostics, Mannheim, Germany).

Anthropometric measurements

In a subset of the total population (88 subjects: 62 females and 26 males), selected to be equally distributed in three categories of BMI (lean, 17.6 < BMI < 25; overweight, 25 <= BMI < 30; obese, BMI >= 30), the percentage of body fat was assessed by dual-energy x-ray absorptiometry (DEXA) (see below).

DEXA (QDR 4500; Hologic Inc., Bedford, MA) measurements were performed as whole body scans, with separate assessment of the three compartments: total fat mass (FM), total lean body mass (LBM), and total bone mineral content. To better define the incidence of adiposity for each subject under study, FM (in kilograms) was divided by lean mass (in kilograms). The calculated parameter was then used for statistical analysis. All DEXA scans were performed by the same skilled laboratory technician.

Adipose tissue studies

RNA extraction and Northern blot analysis. Subcutaneous adipose tissue biopsies were obtained from 20 subjects at the time of elective abdominal surgery. Tissues were frozen in liquid nitrogen and stored at –80 C until use. Total RNA from human adipose tissue was prepared using TriPure TM Isolation Reagent kit (Roche Molecular Biochemicals, Indianapolis, IN) following the manufacturer’s instructions. Six micrograms of total RNA were separated by denaturing formaldehyde electrophoresis and transferred onto nylon membrane (13). Hybridization was performed as described previously (14). For human Hp-PCR-generated probe, we used the primers HpHF 5'-GGTTTCCCACCATAATCTCAC-3' and HpHR 5'-CTGGATGGAAGTCACCTTCA-3', which generated a fragment of 632 bp.

The filter was subsequently rehybridized to a 18S PCR-generated probe, using the primers 18SF 5'-TGACTCAACACGGGAAACCTCAC-3' and 18SR 5'-CGGACATCTAAGGGCATCACAG-3', which generated a fragment of 266 bp.

Autoradiographs were analyzed by a densitometer (GS690; Bio-Rad, Hercules, CA) using MultyAnalyst/PC-PC software for Image Analysis Systems version 1.02 (Bio-Rad).

Protein preparation. Frozen adipose tissue was homogenized in a lysis buffer containing 20 mM Tris (pH 7.5), 150 mM NaCl, 10% glycerol, 1% Triton X-100, 10 mM EDTA, and 1 mM phenylmethylsulfonyl fluoride. The homogenate was then centrifuged at 3000 rpm for 30 min at 4 C. The top and bottom layers were discarded, and the intermediate phase was collected and assayed for the protein concentration by using the Lowry method (Dc protein assay, 500-0114 and 500-0113; Bio-Rad).

Immunoblotting. Proteins were separated on 15% SDS-PAGE and transferred onto a nitrocellulose filter by electroblotting. Filters were saturated with a solution of 4% dry milk in Tris-buffered saline (TBS) and incubated with a polyclonal primary antibody antihuman Hp raised in goat (Sigma 5035; Sigma, St. Louis, MO), at a 1:3000 dilution in TBS + 0.1% Tween with 2% dry milk. After three washes with TBS, the filter was incubated 1 h in the antigoat secondary antibody (horseradish peroxidase conjugated), diluted 1:2000 in TBS + 0.1% Tween + 2% dry milk. Specific protein expression was visualized using a chemiluminescent assay (Amersham Pharmacia/Biotech, Piscataway, NJ), after exposure to x-ray film for 1–5 min.

Statistical analysis

Data are expressed as means ± SD. The StatView SE+ Graphics package (version 3.1, Abacus Concepts Inc., Berkeley, CA) was used to perform univariate and multivariate statistical analysis (Student’s t test, Spearman linear regression, stepwise regression analysis), and a significance limit of P < 0.05 was set.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Serum Hp was positively correlated with BMI (r = 0.38; P < 0.001) and leptin (r = 0.38; P < 0.001) in the whole population (Fig. 1Go). Table 1Go summarizes the clinical and laboratory characteristics of the subjects. Males and females differed significantly for serum leptin (P < 0.001) and blood glucose levels (P < 0.01). Given these differences, the two sexes were analyzed separately, and Table 2Go shows the simple relationships among the various parameters in the whole population and in the two sexes. In females, significant correlations were found between serum Hp and BMI (r = 0.46; P < 0.001), leptin (r = 0.46; P < 0.001), CRP (r = 0.48; P < 0.001), and age (r = 0.18; P < 0.01). In males, a significant correlation was found between Hp and age (r = 0.33; P < 0.01) (Fig. 2Go).



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  		FIG. 1. Regression of serum Hp on BMI (A) and serum leptin (B) in the total population.

 

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  		TABLE 1. Clinical and laboratory parameters of subjects included in the study (means ± SD)

 

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  		TABLE 2. Results of simple regression analysis for each possible pair of the various metabolic and anthropometric variables in the total population (T) and in the female (F) and male (M) groups

 


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  		FIG. 2. Regression of serum Hp on BMI and age in the female (A and B, respectively) and in the male (C and D, respectively) groups. NS, Not significant.

 
As expected in a representative Caucasian population, significant correlations were found between age and BMI and between leptin and BMI (Table 2Go).

In a multivariate stepwise regression analysis, BMI and CRP were independent determinants of serum Hp in females, with BMI having the strongest effect (R2 = 0.29 and 0.13 for BMI and CRP, respectively; total R2 = 0.42). CRP and age were independent determinants of serum Hp in males, but the low values of the correlation coefficients (R2 = 0.12 and 0.07 for CRP and age, respectively; total R2 = 0.19) suggest that these factors account only in part for Hp variability in males. The two sexes showed an apparent discrepancy in the relationship between BMI and serum Hp. This could depend on the different number of subjects in the two samples (221 females vs. 91 males). However, highly significant correlations were observed (data not shown) also when the regression analysis between Hp and BMI was performed in multiple random subsets (n < 100) of the female group, thereby excluding the size of the sample as a critical parameter in this gender discrepancy. Therefore, we analyzed the serum level of Hp against a direct and reliable parameter of adiposity, namely the actual FM.

To gain more direct insights in the relationship between adiposity and serum Hp levels, DEXA scans were obtained in 62 females and 26 males. In this case, serum Hp was positively associated with total body fat both in the female (r = 0.33; P < 0.01) and in the male (r = 0.42; P < 0.05) groups (Fig. 3Go, A and C). Moreover, the degree of correlation became stronger when serum Hp was plotted as a function of body FM adjusted for lean mass (females: r = 0.36, P < 0.005; males: r = 0.64, P < 0.001) (Fig. 3Go, B and D). These data suggest that serum Hp is a marker of adiposity in humans.



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  		FIG. 3. Regression of serum Hp on body fat and body fat/lean mass (as assessed by DEXA) in the female (A and B) and in the male (C and D) groups.

 
The next important issue to study was whether the human adipose tissue might be a source for the production of Hp. The presence of both Hp mRNA and protein was demonstrated by Northern and Western blot analysis in bioptic samples of human abdominal adipose tissue from 20 randomly selected subjects. Figure 4Go displays the results of two representative cases. Differences in the transcript and in the protein size depend on the presence of allele Hp-1 ({alpha}-1 chain) or allele Hp-2 ({alpha}-2 chain). The alleles differ in size for the presence of one (Hp 1) or two (Hp 2) copies of a 1700-bp-long sequence (15). These data indicate that the Hp gene is expressed and that Hp protein is present in the human adipose tissue.



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  		FIG. 4. Hp is present in the human WAT. A, Representative Northern blot analysis showing the presence of Hp mRNA in the human WAT of two subjects. Total RNA was isolated from bioptic samples of abdominal adipose tissue, and 8 µg was loaded in each lane. Equal loading is shown by hybridization of the same filter to the 32P-labeled 18S probe. Differences in transcript size depend on Hp genotype (see Results for details). B, Representative Western blot showing Hp protein expression in human WAT. Total protein extracts (20 µg) were separated by SDS-PAGE and transferred onto nitrocellulose. The blot was probed with antibodies against human Hp and horseradish peroxidase-conjugated secondary antibody. Results identical to those shown in A and B were obtained for all of the 20 samples analyzed.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In the present study, we report for the first time a strong positive correlation between circulating Hp and BMI. Our findings are in line with those of Hannerz et al. (16), who reported that serum Hp was moderately increased in a group of 20 obese female subjects compared with controls, and point to Hp as a possible novel marker of adiposity. Yet, we could not demonstrate a correlation between Hp and BMI in males, analyzed separately. Because this cannot be ascribed to the lower number of males compared with females, an explanation may likely reside in the use of BMI as the independent variable. A more physiological explanation for the different correlations in the two genders may reside in the limited ability of BMI to account for true adiposity. Although BMI is widely used to categorize body weight, it cannot dissect out LBM from adipose tissue, and skeletal muscle is more represented, for any given BMI, in males than in females. Consistent with this hypothesis, a positive association between Hp and total body FM measured by DEXA was demonstrated in both genders. This association was strengthened on adjustment of body FM by lean mass. The higher degree of association may be due to the fact that adjusting for LBM (muscle, vessels, organs) allows a better definition of the distribution volume of Hp. Alternatively, it may be speculated that for a given FM, Hp levels vary as a function of lean mass. Whether this implies an effect of Hp on the modulation of LBM will require more investigation. Taken together, these results support the reliability of serum Hp as a marker of adiposity rather than body size.

A positive relationship was also found between Hp and age. Although worsening of the health conditions in aging may represent a trigger for inflammatory response (17), other mechanisms could be considered. For instance, aging has been associated with a progressive decline in insulin sensitivity and loss of glucose tolerance (18). A strong association has been documented between insulin sensitivity and inflammatory response (19) so that a direct relationship between age and serum Hp levels can be explained by changes in insulin sensitivity.

Data reported here allow us to add Hp to the growing list of circulating protein raised in human obesity and somehow involved in inflammation and/or in immune response, such as TNF-{alpha}, IL-6, CRP, and leptin. The latter has proved to be a key signal in the relationship between obesity and associated complications like infertility (20), diabetes (21), or autoimmune diseases (22). A recent report by Sanna et al. (23) points to leptin as an important signal for linking the metabolic status with the susceptibility for developing experimental autoimmune encephalomyelitis, which serves as a model of human multiple sclerosis. According to their studies, leptin and other cytokines, which are overproduced in obesity, affect the disease-inducing potential of the T cells. A variety of immunomodulatory effects have been attributed to Hp as well, which are supposed to be partly mediated through binding of Hp to the CD11b/CD18 receptor (24, 25). Furthermore, obesity is associated with insulin resistance and increased rate of cardiovascular events (26). Of note is the knowledge that Hp has been related to the development of arterial hypertension (27) and to the incidence of myocardial infarction and stroke (28). Thus, we can speculate that Hp, which is also overproduced in obesity, might constitute a novel link between obesity and some of its comorbidities.

It has already been demonstrated that most of the inflammatory obesity-related proteins are directly produced by the adipose tissue (29). The question raises whether the increased serum levels of Hp in obesity depend on an altered metabolic status affecting Hp release by the liver or on a direct production from the adipose tissue, as already demonstrated in rodents (10). In this regard, the presence of Hp mRNA and protein that we observed in the human WAT strongly suggests that this organ contributes to the increase in circulating Hp levels found in obese individuals. Consistent with our findings, Fain et al. (30) recently reported that Hp is released by explants of human adipose tissue, and this, together with the data reported here, suggests that Hp is a novel adipokine. The simple increase in the adipose mass of obese subjects, due to an hypertrophy and an hyperplasia of the tissue (31), may account for the higher level of serum Hp, although we cannot rule out the possibility that liver participates to this overproduction.

In conclusion, serum Hp constitutes a novel marker of adiposity in humans, and the adipose tissue likely contributes to determine its levels. Here, we speculate that Hp could constitute an important link between obesity and its comorbidities by mediating some of the inflammatory effects associated with the obesity status.


   Acknowledgments
 
We thank the doctors and nurses who took care of the patients participating in this study and Sandro Fornaciai for precious technical assistance during the DEXA measurements.


   Footnotes
 
This work was supported by Compagnia San Paolo and by Ministero dell’Università e della Ricerca (MIUR 2002). C.C., P.B., and J.L.-S. were supported by a Telethon Fellowship. M.M. is an Assistant Telethon Scientist.

Abbreviations: BMI, Body mass index; CRP, C-reactive protein; CV, coefficient(s) of variation; DEXA, dual-energy x-ray absorptiometry; FM, fat mass; Hp, haptoglobin; LBM, lean body mass; WAT, white adipose tissue.

Received November 12, 2003.

Accepted February 23, 2004.


   References
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 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals