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Authors’ Response: Haptoglobin and Body Mass Index

Dulbecco Telethon Institute (C.C., M.M.), and Department of Endocrinology and Metabolism, Section of Endocrinology (C.C., F.S., A.M., P.V., A.P., M.M.), 56126 Pisa, Italy

Address correspondence to: Dr. Margherita Maffei, Dulbecco Telethon Institute, Department of Endocrinology and Metabolism, Ospedale di Cisanello, Via Paradisa, 2, 56126 Pisa, Italy. E-mail: maffeim{at}immr.med.unipi.it.

To the editor:

We thank Taes et al. (1) for raising some interesting issues that allow us to further discuss the results of our study (2).

The first point concerns the source of circulating haptoglobin (Hp). Our study not only shows an association between body mass index (BMI) and serum Hp, but more importantly demonstrates that this association is dependent on the amount of fat mass. The point that serum Hp concentrations are relatively high and that its biological half-life is short simply indicates that Hp production rate is high, irrespective of its source. As already discussed in the manuscript, at present the relative contribution of liver and adipose tissue to the synthesis of serum Hp cannot be established. Similarly, it cannot be defined whether the overproduction of Hp in the obese state derives directly from adipose tissue or whether it is mediated by other adipokines at hepatic level. We favor the first hypothesis based on the following considerations: 1) both Hp mRNA and Hp protein are abundantly expressed in the adipose tissue from humans (see Fig. 4 in Ref. 2) and experimental animals (3, 4, 5); 2) fat mass highly exceeds that of liver, particularly in obese subjects; 3) several studies have compared the gene expression profile in liver in obese and lean animals, and Hp was never identified as a differentially expressed gene (6, 7, 8); and 4) IL-6 (5) and TNF (3), both elevated in serum in obese subjects, are potent inducers of Hp in liver and in adipose tissue as well.

The second issue regards the relationship between serum Hp concentrations and Hp variants. Our study indicates that BMI is an independent determinant of serum Hp, but obviously other variables must intervene to explain the scattered distribution of single values in the BMI–Hp plot. These include individual differences in Hp clearance rate, subtle inflammatory states and, of course, Hp phenotype. Taes et al. (1) suggest that differences in Hp phenotype could influence the relationship between serum Hp and BMI. In this case, not only Hp would be a marker of adiposity, but the Hp gene would somehow regulate the amount of adipose tissue and therefore would be involved in the pathogenesis of obesity. Although this is an interesting hypothesis, it is not supported by experimental evidence at present. As far as our study group is concerned, we have characterized Hp variants in 180 subjects (two of them are shown in Fig. 4 in Ref. 2). As expected, the Hp 1-1 phenotype showed higher serum Hp concentrations, but no significant association could be demonstrated between Hp phenotype and BMI.

Finally, Taes et al. (1) raise doubts about the methodology we used for the Hp assay. In our study, the assessment of serum Hp was performed following instrument calibration against CRM470 standard, and the reference range was 0.3–2.0 g/liter. Indeed, most normal-weight subjects fall within this range, whereas values above 2.0 g/liter belong mainly to obese individuals (see Fig. 1 in Ref. 2), and this is exactly in line with the concept that obesity is a cause for increased concentrations of serum Hp.

In conclusion, we believe that the results of our study fully support the role of serum Hp as a marker for adiposity in humans and that the adipose tissue substantially contributes to Hp overproduction in the obese state.

Received October 14, 2004.

References

1. Taes YEC, De Bacquer D, De Backer G, Delanghe JR 2005 Haptoglobin and body mass index. J Clin Endocrinol Metab 90:594 (Letter)
2. Chiellini C, Santini F, Marsili A, Berti P, Bertacca A, Pelosini C, Scartabelli G, Pardini E, López-Soriano J, Centoni R, Ciccarone AM, Benzi L, Vitti P, Del Prato S, Pinchera A, Maffei M 2004 Serum haptoglobin: a novel marker of adiposity in humans. J Clin Endocrinol Metab 89:2678–2683[Abstract/Free Full Text]
3. Chiellini C, Bertacca A, Novelli SE, Görgün CZ, Ciccarone AM, Giordano A, Xu H, Soukas A, Costa M, Gandini D, Dimitri R, Bottone P, Cecchetti P, Pardini E, Perego L, Navalesi R, Folli F, Benzi L, Cinti S, Friedman JM, Hotamisligil GS, Maffei M 2002 Obesity modulates the expression of haptoglobin in the white adipose tissue via TNF. J Cell Physiol 190:251–258[CrossRef][Medline]
4. Friedrichs WE, Navarijo-Ashbaugh AL, Bowman BH, Yang F 1995 Expression and inflammatory regulation of haptoglobin gene in adipocytes. Bioch Biophys Res Comm 209:250–256[CrossRef][Medline]
5. Do Nascimento CO, Hunter L, Trayhurn P 2004 Regulation of haptoglobin gene expression in 3T3–L1 adipocytes by cytokines, catecholamines, and PPAR. Biochem Biophys Res Commun 313:702–708[CrossRef][Medline]
6. Cohen P, Miyazaki M, Socci ND, Hagge-Greenberg A, Liedtke W, Soukas AA, Sharma R, Hudgins LC, Ntambi JM, Friedman JM 2002 Role for stearoyl-CoA desaturase-1 in leptin-mediated weight loss. Science 297:240–243[Abstract/Free Full Text]
7. Ferrante Jr AW, Thearle M, Liao T, Leibel RL 2001 Effects of leptin deficiency and short-term repletion on hepatic gene expression in genetically obese mice. Diabetes 50:2268–2278[Abstract/Free Full Text]
8. De Fourmestraux V, Neubauer H, Poussin C, Farmer P, Falquet L, Burcelin R, Delorenzi M, Thorens B, Transcript profiling suggests that differential metabolic adaptation of mice to high fat diet is associated with changes in liver to muscle lipid fluxes. J Biol Chem, in press

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