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Serum Haptoglobin: a Novel Marker of Adiposity in Humans

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Serum Haptoglobin: a Novel Marker of Adiposity in Humans 0021-972X/04/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 89(6):2678–2683 Printed in U.S.A. Copyright © 2004 by The Endocrine Society doi: 10.1210/jc.2003-031965 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. LO´ PEZ-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 Downloaded from https://academic.oup.com/jcem/article/89/6/2678/2870304 by guest on 28 September 2021 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 Haptoglobin (Hp) is a glycoprotein involved in the acute phase a modest percentage of the total variability. Serum Hp was response to inflammation. Our previous findings indicate that positively associated with body fat, as assessed by dual-energy Hp mRNA and protein are present in the adipose tissue of x-ray absorptiometry, both in female and in male groups. The rodents and that Hp gene expression is up-regulated in obese level of significance improved when serum Hp was analyzed models. The aim of the present study was to establish whether against fat mass adjusted for lean mass. Finally, Northern and Hp could be considered a marker of obesity in humans. In 312 Western blot analyses performed in biopsies of sc abdominal subjects, serum Hp was correlated directly with body mass fat from 20 obese individuals showed the presence of Hp index (BMI), leptin, C-reactive protein (CRP), and age. In a mRNA and protein in the human adipose tissue. multivariate stepwise regression analysis, BMI and CRP were In conclusion, serum Hp constitutes a novel marker of ad- independent determinants of serum Hp in females, with BMI iposity in humans, and the adipose tissue likely contributes to having the strongest effect. CRP and age were independent determine its levels. (J Clin Endocrinol Metab 89: 2678–2683, determinants of serum Hp in males, although explaining only 2004) N RECENT YEARS, an intriguing theory has looked at of a number of proinflammatory molecules on Hp expression I obesity as a low-grade systemic inflammation condition was assessed in 3T3-L1 adipocytes, and TNF-␣ turned out as (1). This view is supported by several lines of evidence, the strongest inducer. Within the clinical setting, plasma Hp including the association of obesity with elevated serum is a marker of inflammation, its levels increasing significantly levels of C-reactive protein (CRP) (2), IL-6 (3), TNF-␣ (4), and during inflammation, infection, and malignancy (9, 12). leptin (5). Similarly, the acute phase reactant Pentraxin 3, a The aim of the present study was to establish whether Hp member of the pentraxin family closely related to CRP, has can be considered a marker of obesity in humans. Therefore, been found to be up-regulated in the white adipose tissue Hp serum levels were measured in a cohort of lean and (WAT) of different models of murine obesity (6). The adipose overweight/obese subjects and related with several clinical tissue, until recently considered a passive depot of triglyc- and metabolic parameters. erides, is emerging as an important endocrine organ (7) and the source for most of the above-mentioned factors also Subjects and Methods known as adipokines. Study population Along this line of findings, we recently reported that hap- Three hundred twelve (221 females and 91 males) subjects referring toglobin (Hp), a plasma glycoprotein involved in the hepatic to our Endocrinology and Metabolism Department were recruited con- acute phase response to inflammation (8), is present in mu- secutively over a 6-month period. Subjects with hypothyroidism or rine WAT, as described previously by Friedrichs et al. (9), and hyperthyroidism, overt diabetes, adrenal insufficiency or hypercorti- solism, and infectious or malignant disorders were excluded from the that its gene expression is dramatically increased in genet- 2 ically or experimentally induced obese mice (10). study. Body mass index (BMI) and age range were 17.6–57.9 kg/m and ␣ 18–71 yr, respectively. Subcutaneous adipose tissue biopsies were ob- We also identified TNF- as an important signal for the tained from 20 subjects (10 females and 10 males; BMI range, 20.5–45.2 observed obesity-dependent up-regulation. As a matter of kg/m2) at the time of elective open abdominal surgery. For this recruit- fact, obese mice deficient for TNF-␣ or TNF-␣ receptors do ment, we applied the same exclusion criteria mentioned above. The not exhibit the typical increase of Hp mRNA observed in the study protocol was approved by the local Ethical Committee (protocol no. 12327), and patients gave informed consent for their participation in obese controls (10). Moreover, in a recent study (11), the effect the study. Abbreviations: BMI, Body mass index; CRP, C-reactive protein; CV, Laboratory analysis coefficient(s) of variation; DEXA, dual-energy x-ray absorptiometry; Blood samples were obtained by venipuncture after an overnight FM, fat mass; Hp, haptoglobin; LBM, lean body mass; WAT, white fasting, and samples were stored at Ϫ20 C until further analysis. Insulin adipose tissue. was assayed by immunoradiometric assay (Medgenics Diagnostics, JCEM is published monthly by The Endocrine Society (http://www. Fleurus, Belgium), with intraassay and interassay coefficients of varia- endo-society.org), the foremost professional society serving the en- tion (CV) of 4.5 and 10.2%, respectively. Plasma leptin concentration was docrine community. measured by a RIA kit (catalog no. HL-81K; Linco Research, St. Charles, 2678 Chiellini et al. • Haptoglobin in Human Obesity J Clin Endocrinol Metab, June 2004, 89(6):2678–2683 2679 MO) using a polyclonal antibody raised in rabbits against recombinant Spearman linear regression, stepwise regression analysis), and a signif- leptin; the interassay CV was 5–7%. Hp serum concentration was mea- icance limit of P Ͻ 0.05 was set. sured by nephelometry (Dade-Behring, Marburg, Germany), with in- traassay and interassay CV of 2.6 and 6.2%, respectively. CRP serum Results concentration was measured by nephelometry (Dade-Behring), and the intraassay and interassay CV were 2.4 and 4.4%, respectively. Plasma Serum Hp was positively correlated with BMI (r ϭ 0.38; glucose was measured on fluorinated plasma samples (Gluco-quant, P Ͻ 0.001) and leptin (r ϭ 0.38; P Ͻ 0.001) in the whole Roche/Hitachi modular analyzer; Roche Diagnostics, Mannheim, population (Fig. 1). Table 1 summarizes the clinical and lab- Germany). oratory characteristics of the subjects. Males and females differed significantly for serum leptin (P Ͻ 0.001) and blood Anthropometric measurements glucose levels (P Ͻ 0.01). Given these differences, the two In a subset of the total population (88 subjects: 62 females and 26 sexes were analyzed separately, and Table 2 shows the sim- males), selected to be equally distributed in three categories of BMI (lean, Ͻ Ͻ Յ Ͻ Ն ple relationships among the various parameters in the whole 17.6 BMI 25; overweight, 25 BMI 30; obese, BMI 30), the Downloaded from https://academic.oup.com/jcem/article/89/6/2678/2870304 by guest on 28 September 2021 percentage of body fat was assessed by dual-energy x-ray absorptiom- population and in the two sexes. In females, significant cor- etry (DEXA) (see below). relations were found between serum Hp and BMI (r ϭ 0.46; DEXA (QDR 4500; Hologic Inc., Bedford, MA) measurements were P Ͻ 0.001), leptin (r ϭ 0.46; P Ͻ 0.001), CRP (r ϭ 0.48; P Ͻ performed as whole body scans, with separate assessment of the three 0.001), and age (r ϭ 0.18; P Ͻ 0.01). In males, a significant compartments: total fat mass (FM), total lean body mass (LBM), and total ϭ P Ͻ bone mineral content. To better define the incidence of adiposity for each correlation was found between Hp and age (r 0.33; subject under study, FM (in kilograms) was divided by lean mass (in 0.01) (Fig. 2). kilograms). The calculated parameter was then used for statistical anal- As expected in a representative Caucasian population, ysis. All DEXA scans were performed by the same skilled laboratory significant correlations were found between age and BMI technician. and between leptin and BMI (Table 2). In a multivariate stepwise regression analysis, BMI and Adipose tissue studies CRP were independent determinants of serum Hp in fe- 2 ϭ RNA extraction and Northern blot analysis. Subcutaneous adipose tissue males, with BMI having the strongest effect (R 0.29 and biopsies were obtained from 20 subjects at the time of elective abdominal 0.13 for BMI and CRP, respectively; total R2 ϭ 0.42). CRP and surgery. Tissues were frozen in liquid nitrogen and stored at Ϫ80 C until age were independent determinants of serum Hp in males, use. Total RNA from human adipose tissue was prepared using TriPure but the low values of the correlation coefficients (R2 ϭ 0.12 TM Isolation Reagent kit (Roche Molecular Biochemicals, Indianapolis, 2 ϭ IN) following the manufacturer’s instructions. Six micrograms of total and 0.07 for CRP and age, respectively; total R 0.19) RNA were separated by denaturing formaldehyde electrophoresis and suggest that these factors account only in part for Hp vari- transferred onto nylon membrane (13). Hybridization was performed as described previously (14).
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