Martinclodi.at

Plasma Osteopontin Increases After Bariatric Surgery
and Correlates with Markers of Bone Turnover But
Not with Insulin Resistance
Michaela Riedl, Greisa Vila, Christina Maier, Ammon Handisurya, Soheila Shakeri-Manesch,Gerhard Prager, Oswald Wagner, Alexandra Kautzky-Willer, Bernhard Ludvik, Martin Clodi, andAnton Luger Division of Endocrinology and Metabolism, Department of Medicine III (M.R., G.V., C.M., A.H., A.K.-W., B.L., M.C., A.L.), Division ofGeneral Surgery, Department of Surgery (S.S.-M., G.P.), and Clinical Institute of Medical and Chemical Laboratory Diagnostics (O.W.),Medical University of Vienna, A-1090, Vienna, Austria Context: Osteopontin (OPN) is a multifunctional protein involved in bone metabolism, cardiovas-
cular disease, diabetes, and obesity. OPN levels are elevated in the plasma and adipose tissue of
obese subjects, and are decreased with diet-induced weight loss.
Objective: We investigated the effect of bariatric surgery on plasma OPN concentrations in mor-
bidly obese patients.
Setting: The study was performed at a university hospital.
Subjects: We investigated 40 obese patients aged 43.1 Ϯ 1.8 yr, scheduled to undergo bariatric
surgery. Roux-en-Y gastric bypass (RYGB) was performed in 30 subjects (27 females, three males),
and laparoscopic adjustable gastric banding (LAGB) in 10 subjects (eight females, two males).
Study Design: All patients were studied before and 1 yr (10.3–14.8 months) after the intervention.
Main Outcome Measures: OPN, leptin, C-reactive protein, insulin, the homeostatic model assess-
ment insulin resistance index, calcium, 25-hydroxyvitamin D, C telopeptide, and osteocalcin were
determined.
Results: Both bariatric procedures significantly reduced body weight, body mass index, insulin,
leptin, and C-reactive protein 1 yr after surgery. Plasma OPN increased from 31.4 Ϯ 3.8 to 52.8 Ϯ
3.7 ng/ml after RYGB (P Ͻ 0.001) and from 29.8 Ϯ 6.9 to 46.4 Ϯ 10.6 ng/ml after LAGB (P ϭ 0.042).
Preoperative OPN correlated with age, insulin, the homeostatic model assessment insulin resis-
tance index, and postoperative OPN. Postoperative OPN correlated with C telopeptide and
osteocalcin.
Conclusions: One year after RYGB and LAGB, plasma OPN levels significantly increased and cor-
related with biomarkers of bone turnover. Unlike other proinflammatory cytokines, OPN does not
normalize but increases further after bariatric surgery. (J Clin Endocrinol Metab 93: 2307–2312,
2008)
Osteopontin (OPN) is a conserved multifunctional glyco- integrinsandCD44variants(2,4).OPNcontrolsboneremod-
protein that is secreted by many cell types (1–3). Its struc- eling, and functions as a proinflammatory cytokine in regulating ture contains several signaling motifs that allow binding to cal- immune processes, chronic inflammation, and tumorigenesis (1, cium and adhesion to different membrane receptors, including Abbreviations: BMI, Body mass index; CRP, C-reactive protein; HOMA, homeostatic model assessment; LAGB, laparoscopic adjustable gastric banding; LDL, low-density lipoprotein;OC, osteocalcin; OPN, osteopontin; RYGB, Roux-en-Y gastric bypass.
Copyright 2008 by The Endocrine Society doi: 10.1210/jc.2007-2383 Received October 25, 2007. Accepted March 5, 2008.
J Clin Endocrinol Metab, June 2008, 93(6):2307–2312 J Clin Endocrinol Metab, June 2008, 93(6):2307–2312 Recently, several studies have highlighted the involvement of Subjects and Methods
OPN in certain components of the metabolic syndrome: plasmaOPN is elevated in cardiovascular disease (9), diabetes (10), and Study subjects
in obese subjects when compared with an age-matched normal A total of 40 Caucasians with morbid obesity was recruited from the cohort scheduled for bariatric surgery. Exclusion criteria were: age less control group (11, 12). OPN expression is increased in the pres- then 18 yr, previous bariatric surgery or recent (greater than 5%) weight ence of elevated proinflammatory cytokine concentrations (1) change, diabetes mellitus (21), uncontrolled hypertension, myocardial and hyperglycemia (13) but decreases after treatment with per- infarction during the last year, chronic kidney or liver disease, and thy- oxisome proliferator-activated receptor-␣ agonists (14). In ad- roid disease and malignancy. The study was approved by the institutionalreview board, and informed consent was obtained from all participants dition, OPNϪ/Ϫ mice on a high-fat diet displayed reduced adi- pose tissue inflammation and improved insulin resistance when RYGB was performed in 30 patients (27 females and three males, compared with the wild-type controls (15).
aged 42.9 Ϯ 2 yr) and LAGB in 10 patients (eight females and two males, Diet-induced weight loss in obese subjects is associated aged 43.9 Ϯ 4.5 yr). Both procedures were performed at a university with normalization, namely reduction, of plasma OPN con- hospital by the same team of surgeons. Among the 35 women studied, 23were premenopausal (18 in the RYGB group and five in the LAGB group) centrations (11). To our knowledge there is no evidence on the and 12 postmenopausal (nine in the RYGB group and three in the LAGB effect of bariatric surgery on this complexly regulated mole- group). Only two women were taking oral contraceptives (RYGB cule. Bariatric procedures are increasingly used as the treat- group). Patients were prescribed supplementations of vitamin D and ment of choice for morbid obesity because they achieve sig- calcium (one tablet containing 600 mg calcium and 400 IU vitamin D3,twice daily) throughout the post-surgery study period. Data were col- nificant weight loss and reduce mortality rates (16). The lected at two time points: before bariatric surgery and 1 yr after bariatric reduction in mortality rate is attributed to a considerable re- surgery. The time elapsed between the two time points varied from 10.3– duction in comorbidities such as cardiovascular disease, dia- 14.8 months. At each visit, subjects underwent a thorough clinical ex- betes, and cancer (17). Loss of adipose tissue mass is accom- amination, and blood samples were collected in the fasting state. Fasting panied by a decrease in insulin resistance, and in plasma glucose, triglycerides, total cholesterol, low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein-cholesterol, albumin, calcium, 25- concentrations of adipokines, inflammatory markers and cy- hydroxyvitamin D, creatinine, liver enzymes, and C-reactive protein tokines (18). Nevertheless, bariatric surgery procedures are (CRP) were quantified using routine certified tests.
complicated by gastrointestinal complaints, bone resorption,and bone loss (18, 19). Accumulating evidence has revealed Measurement of hormones and bone markers
that weight regain happens in the long term (20).
PTH, osteocalcin (OC), and C telopeptide (␤-crosslaps, C-terminal The present study aimed to investigate the changes in telopeptide of type I collagen, CTX) were routinely determined by elec- plasma OPN 1 yr after two commonly used bariatric proce- trochemiluminescence immunoassays (Elecsys; Roche Diagnostics,Mannheim, Germany). For the other parameters, blood samples were dures: laparoscopic adjustable gastric banding (LAGB), a immediately cooled, centrifuged within 30 min, and then frozen at Ϫ80 strictly restrictive procedure; and laparoscopic Roux-en-Y C. Samples taken on both study days from an individual subject were gastric bypass (RYGB), a mixed restrictive malabsorptive pro- analyzed in one assay and in duplicates. Plasma OPN was measured using cedure. Prompted by the association of OPN with metabolic a commercially available sandwich immunoassay (quantikine ELISA kit;R&D Systems, Inc., Minneapolis, MN), with an intraassay and interas- diseases, inflammation, and bone metabolism, we explored say coefficient of variation of 2.9 and 5.4%, respectively. Leptin was the changes in metabolic, inflammatory, and bone turnover measured using the Fluorokine human leptin kit and the obesity Multi- Analyte Profiling Base Kit (R&D Systems). Insulin and C peptide were Clinical and biochemical parameters of obese subjects before and 1 yr after bariatric surgery RYGB group (n ؍ 30)
LAGB group (n ؍ 10)
Pb
Baseline
Pa
Baseline
Pa
Data are presented as mean Ϯ SE. HDL, High-density lipoprotein.
a P values for comparison between baseline and postoperative values (paired t test).
b P values for comparison between surgery-induced changes in the RYGB and LAGB groups (Mann-Whitney U test).
J Clin Endocrinol Metab, June 2008, 93(6):2307–2312 Hormone and peptide plasma levels of obese subjects before and 1 yr after bariatric surgery RYGB group (n ؍ 30)
LAGB group (n ؍ 10)
Pb
Baseline
After surgery
Pa
Baseline
After surgery
Pa
Normal ranges: PTH, 15– 65; and TSH, 0.44 –3.77.
a P values for comparison between baseline and postoperative values (paired t test).
b P values for comparison between surgery induced changes in the RYGB and LAGB groups (Mann-Whitney U test).
determined using commercially available RIAs (LINCO Research, Inc., related with both OC (Fig. 2, E and F) and C telopeptide (Fig. 2, St. Charles, MO). The homeostatic model assessment (HOMA) insulin resistance index was calculated as the product of fasting glucose (ex- The difference between OPN levels at both study time points pressed as mg/dl) and insulin (expressed as ␮U/ml) divided by the con- was negatively associated with the difference in plasma albumin (R2 ϭ 0.106; P ϭ 0.046). There were no significant correlations Statistical analysis
between OPN and the remaining parameters that were studied.
All data are expressed as mean Ϯ SEM. Baseline and postoperative values were compared using the paired Student’s t test. Surgery inducedchanges between the two groups (LABG vs. RYGB) were tested with the Discussion
Mann-Whitney U test. Linear regression analysis was performed to eval-uate the relationships between OPN and other parameters. The statistical We show here that plasma OPN levels increase significantly and software package SPSS release 12.0.1 (SPSS, Inc., Chicago, IL) was used.
P values less than 0.05 were considered statistically significant.
correlate to biomarkers of bone turnover 1 yr after RYGB and Preoperative values and RYGB- and LAGB-induced changes of clinical and biochemical parameters are presented in Table 1.
Baseline characteristics were similar between the two groups.
Both surgical procedures significantly decreased weight, body mass index (BMI), plasma insulin, CRP, and leptin (Tables 1 and 2). The reduction in the HOMA insulin resistance index, tri- glycerides, total cholesterol, LDL-cholesterol, and albumin reached significant levels only in the RYGB group.
Plasma OPN increased from 31.4 Ϯ 3.8 to 52.8 Ϯ 3.7 ng/ml after RYGB (P Ͻ 0.001) and from 29.8 Ϯ 6.9 to 46.4 Ϯ 10.6 ng/ml after LAGB (P ϭ 0.042) (Fig. 1, A and B, and Table 2). Ctelopeptide (marker of bone resorption) and OC (marker of bone formation) also increased in both groups after surgery (Table 2),whereas total calcium and PTH did not change significantly (Ta- bles 1 and 2). TSH showed a mild but significant decrease in the There was a weak but significant negative correlation of base- line OPN levels with age (Fig. 2A), but no relation to menopausal status in women. Preoperative plasma OPN concentrations cor- related positively and highly significantly to the respective post- At baseline, plasma OPN levels correlated positively to insu- lin (R2 ϭ 0.205; P ϭ 0.003) and the HOMA insulin resistance index (R2 ϭ 0.154; P ϭ 0.024). However, both of these associ- ations disappeared 1 yr after bariatric surgery (Fig. 2, C and D).
FIG. 1. Bariatric surgery induced changes in plasma OPN. Differences
In addition, preoperative values of OPN were not associated between preoperative and postoperative OPN plasma concentrations with markers of bone turnover, whereas postoperative OPN cor- J Clin Endocrinol Metab, June 2008, 93(6):2307–2312 groups should be kept in mind when inter- been previously reported (Fig. 2A). A pos- sible link with age-related changes in bone mineral density is hypothetical and remains to be investigated. Of the patients studied (22). Increased levels of cytokines, activa- tion of the hypothalamic-pituitary-adrenal which promotes macrophage adhesion andmigration in vitro (6). Recently, Go´mez- Ambrosi et al. (11) showed that obese pa- levels decline after diet-induced weight loss.
Within the adipose tissue, OPN expression is restricted to adipose tissue macrophages tion, and insulin resistance when compared with their wild-type counterparts (15). It is tant player in the pathophysiology of adi- pose tissue inflammation and cytokine-in- (23). In addition, it reduces the amount of adipose tissue macrophages as well as the expression of genes involved in macrophage FIG. 2. Linear regression analysis of correlations between plasma OPN and other variables. A,
Baseline OPN vs. age. B, Preoperative OPN vs. postoperative OPN. C, Preoperative plasma insulin receptor, and colony stimulating factor.
vs. preoperative OPN. D, Postoperative plasma insulin vs. postoperative OPN. E, Preoperative Taking these data together, we expected a plasma OC vs. preoperative OPN. F, Postoperative plasma OC vs. postoperative OPN. G,Preoperative plasma C telopeptide vs. preoperative OPN. H, Postoperative plasma C telopeptide postoperative decrease in plasma OPN. The opposite finding presented in this study doesnot seem to have a direct association with LAGB. Bariatric surgery achieved a significant reduction in body the accompanied weight loss and reduction in insulin resistance.
weight, BMI, leptin, insulin, and CRP, however, OPN changes or When discussing the origin of elevated circulating OPN after postoperative values were not correlated to these variables.
bariatric surgery, we should keep in mind that known substantial RYGB (n ϭ 30) was more effective than LAGB (n ϭ 10) in sources are osteoblasts, endothelial and epithelial cells, macro- reducing weight, BMI, insulin, the HOMA insulin resistance in- phages, and cancer cells (2). Bariatric surgery procedures are dex, total cholesterol, and LDL cholesterol. The effects on OPN complicated by bone loss and increased markers of bone turn- and markers of bone turnover were not significantly different over (18, 20). We found a significant correlation between post- between the two surgical procedures. Nevertheless, the differ- operative OPN values and markers of bone turnover (Fig. 2, J Clin Endocrinol Metab, June 2008, 93(6):2307–2312 E–H), and, therefore, hypothesize that bone might be the source tion of energy metabolism by the skeleton merits further of high plasma OPN concentrations 1 yr after bariatric surgery.
Indeed, many studies have already established a strong associa- In conclusion, we report here that plasma OPN, a proinflam- tion between obesity surgery and bone loss (18, 19). OPN rep- matory cytokine linked to the development of insulin resistance, resents a component of the noncollagenous bone matrix secreted increases 1 yr after RYGB and LAGB. It is suggested that bone by osteoblasts and osteoclasts that is critical for the remodeling might be the source of enhanced OPN concentrations. Further of mature bone (1). Bone remodeling is the outcome of two se- prospective studies are needed to elucidate whether postopera- quential events: resorption of preexisting bone by osteoclasts and tive circulating OPN concentrations, and/or the degree of bone de novo bone formation by osteoblasts (24). OPN is secreted loss, relate to future changes in body weight and insulin from both osteoclasts and osteoblasts (1). OPN deficient mice have impaired bone resorption and hypermineralized fragilebones (25, 26). Therefore, increased OPN levels after gastricsurgery might be under the control of the same mechanisms that Acknowledgments
Body weight is an important determinant of bone mass (27).
We thank Dr. Maximilian Zeyda for helpful discussions and comments Several studies have found an association of high body weight with higher bone mass and with lower bone loss (28). This re- Address all correspondence and requests for reprints to: Michaela lationship seems to be also dependent on age and sex (29). Fat Riedl, Department of Medicine III, Medical University of Vienna, tissue is an endocrine organ that releases adipokines, such as Waehringer Guertel 18-20, A-1090, Vienna, Austria. E-mail: leptin, which influence not only the peripheral insulin sensitivity, but also the function of many organs (30). Leptin regulates os- This study was supported by an unrestricted research grant from teoblast proliferation and bone formation by acting at the hy- Disclosure Statement: The authors have nothing to disclose.
pothalamus, and through a combined regulation of two antag-onistic pathways (31, 32). Serum leptin level is a significant andindependent predictor of bone mineral density in postmeno-pausal women (33). Moreover, epidemiological data from 800 References
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