Surg Endosc DOI 10.1007/s00464-014-3490-1
and Other Interventional Techniques
Comparative effects of gastric bypass and sleeve gastrectomy on plasma osteopontin concentrations in humans Andoni Lancha • Rafael Moncada • Vı´ctor Valentı´ • Amaia Rodrı´guez • Victoria Catala´n • Sara Becerril • Beatriz Ramı´rez • Leire Me´ndez-Gime´nez Marı´a J. Gil • Fernando Rotellar • Secundino Ferna´ndez • Javier Salvador • Gema Fru¨hbeck • Javier Go´mez-Ambrosi
•
Received: 30 October 2013 / Accepted: 14 February 2014 Ó Springer Science+Business Media New York 2014
Abstract Background Bariatric surgery (BS) has proven to be an effective treatment for morbid obesity. Osteopontin (OPN) is a proinflammatory cytokine involved in the development of obesity. The aim of our study was to determine the effect of weight loss following BS on circulating levels of OPN in humans. Methods Body composition and circulating concentrations of OPN and markers of bone metabolism were determined in obese patients who underwent Roux-en-Y gastric bypass (RYGB; n = 40) or sleeve gastrectomy (SG; n = 11). Results Patients who underwent RYGB or SG showed decreased body weight (P \ 0.001) and body fat percentage (P \ 0.001) as well as lower insulin resistance. However, plasma OPN levels were significantly increased after RYGB (P \ 0.001) but remained unchanged following SG (P = 0.152). Patients who underwent RYGB also showed significantly increased C-terminal telopeptide of type-I collagen (ICTP) (P \ 0.01) and osteocalcin (P \ 0.001) while bone mineral density tended to decrease
(P = 0.086). Moreover, OPN concentrations were positively correlated with the bone resorption marker ICTP after surgery. On the other hand, patients who underwent SG showed significantly increased ICTP levels (P \ 0.05), and the change in OPN was positively correlated with the change in ICTP and negatively with the change in vitamin D after surgery (P \ 0.05). Conclusions RYGB increased circulating OPN levels, while they remained unaltered after SG. The increase in OPN levels after RYGB could be related to the increased bone resorption in relation to its well-known effects on bone of this malabsorptive procedure in comparison to the merely restrictive SG.
A. Lancha A. Rodrı´guez V. Catala´n S. Becerril B. Ramı´rez L. Me´ndez-Gime´nez G. Fru¨hbeck J. Go´mez-Ambrosi (&) Metabolic Research Laboratory, Clı´nica Universidad de Navarra, Irunlarrea 1, 31008 Pamplona, Spain e-mail: [email protected]
V. Valentı´ F. Rotellar Department of Surgery, Clı´nica Universidad de Navarra, 31008 Pamplona, Spain
A. Lancha V. Valentı´ A. Rodrı´guez V. Catala´n S. Becerril B. Ramı´rez L. Me´ndez-Gime´nez M. J. Gil F. Rotellar S. Ferna´ndez J. Salvador G. Fru¨hbeck J. Go´mez-Ambrosi CIBER Fisiopatologı´a de la Obesidad y Nutricio´n (CIBERobn), Instituto de Salud Carlos III, 31008 Pamplona, Spain R. Moncada Department of Anesthesia, Clı´nica Universidad de Navarra, 31008 Pamplona, Spain
Keywords Osteopontin Roux-en-Y gastric bypass Sleeve gastrectomy Bone The prevalence of obesity has increased over recent decades to become a true pandemic [1]. Currently, in Western countries, like the United States, more than 35 % of the
M. J. Gil Department of Biochemistry, Clı´nica Universidad de Navarra, 31008 Pamplona, Spain S. Ferna´ndez Department of Otorhinolaryngology, Clı´nica Universidad de Navarra, 31008 Pamplona, Spain J. Salvador G. Fru¨hbeck Department of Endocrinology & Nutrition, Clı´nica Universidad de Navarra, 31008 Pamplona, Spain
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population is obese [2]. Obesity is associated with several pathologies such as hypertension, type 2 diabetes, fatty liver, hyperlipidemia, and cancer, increasing morbidity and mortality [3]. Indeed, weight loss has been associated with an improvement of the obesity-associated comorbidities [4–7]. Bariatric surgery (BS) has been proven to be effective for reducing body weight in obese patients [8, 9]. Roux-enY gastric bypass (RYGB) and sleeve gastrectomy (SG) are now routinely performed surgical techniques for morbidly obese patients [10–12] that improve obesity-associated comorbidities as well as extend life expectancy [13, 14]. Obesity is associated with a chronic state of low-grade chronic inflammation characterized by the abnormal expression of cytokines such as tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), serum amyloid A (SAA), adiponectin, and osteopontin (OPN), among others [15–17]. BS reduces the levels of circulating proinflammatory proteins such as C-reactive protein (CRP), IL-6, IL-18, monocyte chemoattractant protein-1 (MCP-1), and calprotectin, among others, at the same time as increasing the levels of adiponectin (an anti-inflammatory adipokine) [18–21]. BS further reduces the expression of proinflammatory proteins such as TNF-a and CD68 in adipose tissue [18, 22]. These changes may contribute to the improvement in obesityassociated comorbidities after surgery-induced weight loss. OPN was initially identified as a protein of the bone extracellular matrix. However, OPN is expressed in multiple cell types such as osteoclasts, osteoblasts, epithelial cells, and endothelial cells, as well as in cells from the nervous and immune systems [23]. OPN is implicated in bone metabolism, wound healing, immune and inflammatory responses, cancer, kidney physiology, respiratory diseases, and cardiovascular and atherosclerotic processes as well as in the development of diabetes and hepatic steatosis [24–28]. Several studies have demonstrated that OPN is also produced by adipose tissue and that its expression increases in adipose tissue in human obesity [15, 22, 29]. In this sense we have observed that diet-induced weight loss decreased OPN plasma concentrations [15]. However, other studies have reported that plasma OPN levels increase after weight loss due to BS [22, 30, 31]. The aim of the present study was to compare OPN plasma concentrations after RYGB and SG in humans.
Materials and methods Subjects In order to analyze the effect of weight loss achieved by BS on plasma OPN concentrations, 40 obese Caucasian subjects (8 male/32 female) undergoing RYGB and 11 obese
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Caucasian subjects (4 male/7 female) undergoing SG were recruited from patients attending the Department of Endocrinology and Nutrition and the Department of Surgery at the Clı´nica Universidad of Navarra. All the individuals included in the study exhibited a body mass index (BMI) greater than 35 kg/m2. Patients underwent a clinical assessment, including physical examination and body composition analysis, performed by a multidisciplinary team. Patients with signs of infection were excluded. All subjects were nonsmokers. Obese patients were not taking statins and diabetic or antihypertensive medication. Following European guidelines, daily oral vitamin and micronutrient supplements were routinely prescribed to all patients who underwent RYGB, to compensate for their possible reduced intake and absorption, but not to those who underwent SG, given that this is a restrictive technique and not a malabsorptive procedure [32]. The interventions were performed via a laparoscopic approach. The experimental design was approved, from an ethical and scientific standpoint, by the hospital’s Ethical Committee responsible for research. Volunteers signed informed consent to participate in the study. Anthropometric measurements Body weight was measured with a digital scale to the nearest 0.1 kg, and height was measured to the nearest 0.1 cm with a Holstein stadiometer (Holstein Ltd., Crimes, UK). BMI was calculated as weight in kg divided by the square of height in meters. Body fat was estimated by airdisplacement plethysmography (Bod-PodÒ, Life Measurements, Concord, CA, USA) as previously described [33, 34]. Excess weight loss (EWL) was calculated as weight loss divided by the excess weight. Analytical procedures Blood samples were collected after an overnight fast in the morning in order to avoid potential confounding influences due to hormonal rhythmicity. Plasma glucose was analyzed using an automated analyzer (Roche/Hitachi Modular P800, Basel, Switzerland) as previously described [35]. Insulin was measured by means of an enzyme-amplified chemiluminescence assay (Immulite, Diagnostic Products Corp., Los Angeles, CA, USA). Insulin resistance was determined by means of the homeostatic model assessment (HOMA) index expressed as glucose (mmol/L) 9 insulin (lU/mL)/22.5 [36]. Insulin sensitivity was calculated by using the quantitative insulin sensitivity check index (QUICKI) [37]. This index is a simple accurate method for assessing insulin sensitivity in humans and is defined as 1/ (log[insulin0] ? log[glucose0]). Total cholesterol and triglyceride concentrations were determined by enzymatic
Surg Endosc
spectrophotometric methods (Roche, Basel, Switzerland). High-density-lipoprotein (HDL) cholesterol was quantified by a colorimetric method in a Beckman Synchron CX analyzer (Beckman Instruments, Ltd., Bucks, UK). Lowdensity-lipoprotein (LDL) cholesterol was calculated using the Friedewald formula [35]. Calcium and phosphate were analyzed by colorimetric methods. Uric acid, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, c-glutamyl transferase (c-GT), and creatinine were measured by enzymatic tests (Roche) in an automated analyzer (Roche/Hitachi Modular P800). Fibrinogen concentrations were determined according to the method of Clauss using a commercially available kit (Hemoliance, Instrumentation Laboratory, Barcelona, Spain). Measurement of von Willebrand factor antigen was performed by a microlatex immunoassay (Diagnostica Stago, Inc., Parsippany, NJ, USA). A standard curve was prepared with a universal reference (NISBC 91/666) and the results were expressed as percentage of the standard. Intra- and interassay coefficients of variation (CV) were 4.0 and 8.0 %, respectively. Parathyroid hormone (PTH) and osteocalcin were analyzed by chemiluminescent methods with an Immulite 2500 (Siemens AG, Erlagen, Germany). High-sensitivity CRP was measured using the Tina-quant CRP (Latex) ultrasensitive assay (Roche). Leptin (Linco Research, Inc., St. Charles, MO, USA) was quantified by a double-antibody RIA method. Intra- and interassay CV were 5.0 and 4.5 %, respectively. C-terminal telopeptide of type-I collagen (ICTP) was measured by RIA (Orion Diagnostica, Espoo, Finland). Intra- and interassay CV were 4.8 and 5.6 %, respectively. 25-Hydroxyvitamin D was quantified by ELISA (Immundiagnostik AG, Bensheim, Germany), with intra- and interassay CV of 10.7 and 11.8 %, respectively. OPN was determined by ELISA (R&D Systems Inc., Minneapolis, MN, USA) with intra- and interassay CV of 3.2 and 5.9 %, respectively. Bone mineral density (BMD) measurements BMD was measured at the lumbar spine (L2–L4) by dualenergy X-ray absorptiometry (DEXA) using a Lunar iDXA (GE Healthcare Lunar, Madison, WI, USA) as previously described [15]. Statistical analysis Data are presented as mean ± standard deviation (SD). Sample size was estimated using the program PS Power and Sample Size Calculations (edition 2.1.30). The effect of weight loss after RYGB was analyzed by two-tailed paired t tests. Correlations between two variables were assessed by Pearson’s correlation coefficient. The
calculations were performed using the SPSS for Windows ver. 15.0.1 (SPSS, Inc., Chicago, IL, USA). A P value less than 0.05 was considered statistically significant.
Results Effect of weight loss by RYGB on plasma OPN concentrations in obese patients After an average of 15 months following RYGB, patients showed a significant (P \ 0.001) decrease in body weight, BMI, and body fat percentage, as well as a significant improvement in glycemia (P \ 0.001), insulinemia (P \ 0.001), and HOMA and QUICKI indices (P \ 0.001) (Table 1). Triglyceride (P \ 0.001) as well as total (P \ 0.001) and LDL cholesterol (P \ 0.001) concentrations were significantly reduced, while HDL cholesterol levels were increased (P \ 0.001). Leptin and CRP concentrations were also notably improved (P \ 0.001). An increase in the levels of calcium (P \ 0.01), phosphate (P \ 0.001), vitamin D (P \ 0.001), osteocalcin (P \ 0.001), and ICTP (P \ 0.001) as well as a decrease in the concentrations of PTH (P \ 0.01) were observed (Table 1). BMD tended to decrease from 1.052 ± 0.126 to 1.026 ± 0.161 g/cm2 after RYGB, although the differences did not reach statistical significance (P = 0.086). Circulating OPN concentrations were significantly increased (P \ 0.001) after RYGB (Fig. 1). Before RYGB, circulating OPN concentrations were positively correlated with plasma PTH (r = 0.38; P \ 0.05) and calcium (r = 0.42; P \ 0.05) levels (Table 2). Interestingly, circulating OPN levels were positively correlated with the marker of bone resorption ICTP (r = 0.40; P \ 0.05), and with alkaline phosphatase (r = 0.50; P \ 0.01) concentrations after surgery. The change in the circulating levels of OPN after surgery also showed a trend toward a positive correlation with the change in ICTP levels (r = 0.31; P = 0.081). Moreover, OPN concentrations were positively correlated with insulin levels (r = 0.42; P \ 0.05) and HOMA index (r = 0.36; P \ 0.05) after surgery. The change in the circulating levels of OPN after the operation showed a positive correlation with the change in plasma fibrinogen (r = 0.49; P \ 0.01) and CRP (r = 0.51; P \ 0.05) levels and a negative correlation with the change in the QUICKI index (r = -0.41; P \ 0.05). Effect of weight loss by SG on plasma OPN concentrations in obese patients One year after the operation, patients who underwent SG showed a significant decrease (P \ 0.001) in body weight, BMI, and body fat percentage (Table 1). There was also a
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Surg Endosc Table 1 Effect of surgically induced weight loss in obese patients RYGB Before WL Sex (male/female)
8/32
SG After WL –
Age (years)
38.7 ± 13.5
40.4 ± 13.4
Body weight (kg)
123 ± 30
80 ± 19
2
P
Before WL – –
\0.001
After WL
4/7
–
44.3 ± 10.5
45.5 ± 10.3
113 ± 20
80 ± 20
P – – \0.001
BMI (kg/m )
45.2 ± 7.9
29.5 ± 5.2
\0.001
40.4 ± 6.1
29.2 ± 5.7
\0.001
Body fat (%)
51.7 ± 6.2
33.0 ± 10.3
\0.001
47.6 ± 6.8
35.1 ± 9.1
\0.001
EWL (%) Waist circumference (cm) Waist-to-hip ratio Glucose (mmol/L) Insulin (pmol/L)
– 120 ± 16 0.90 ± 0.08
72.3 ± 17.9 92 ± 13 0.86 ± 0.07
– \0.001 \0.001
– 125 ± 13 1.02 ± 0.09
64.8 ± 25.4 100 ± 16 0.95 ± 0.11
– \0.001 \0.05
5.38 ± 0.97
4.56 ± 0.51
\0.001
7.74 ± 4.01
5.46 ± 1.38
\0.05
120.3 ± 68.8
50.2 ± 24.5
\0.001
229.1 ± 251.7
64.5 ± 54.8
\0.05
HOMA
4.3 ± 2.6
1.3 ± 0.8
\0.001
13.1 ± 7.5
2.7 ± 2.5
\0.05
QUICKI
0.319 ± 0.026
0.372 ± 0.037
\0.001
0.294 ± 0.054
0.362 ± 0.062
\0.05
1.32 ± 0.46
0.90 ± 0.29
\0.001
1.72 ± 1.18
1.24 ± 0.60
Triglycerides (mmol/L)
0.054
Total cholesterol (mmol/L)
5.25 ± 1.01
4.01 ± 0.91
\0.001
4.75 ± 0.62
4.94 ± 0.61
0.357
LDL-cholesterol (mmol/L)
3.38 ± 0.81
2.29 ± 0.62
\0.001
2.82 ± 0.53
2.94 ± 0.70
0.457
HDL-cholesterol (mmol/L)
1.06 ± 0.22
1.31 ± 0.49
\0.001
1.13 ± 0.26
1.44 ± 0.47
0.053
5.7 ± 1.5
4.3 ± 1.0
\0.001
4.9 ± 1.3
4.7 ± 1.4
0.541
Uric acid (mg/dL) Fibrinogen (mg/dL)
323 ± 88
321 ± 71
0.484
352 ± 86
311 ± 80
0.206
von Willebrand factor (%)
125 ± 61
121 ± 42
0.192
98 ± 41
76 ± 29
0.509
C-reactive protein (mg/L)
9.6 ± 6.1
2.3 ± 3.3
\0.001
6.3 ± 3.4
1.5 ± 1.1
ALT (U/L)
26 ± 18
20 ± 9
0.061
23 ± 15
14 ± 4
15 ± 7 106 ± 26
15 ± 4 110 ± 31
0.896 0.586
15 ± 10 79 ± 31
13 ± 2 53 ± 15
0.132 \0.05
20 ± 10
10 ± 5
\0.001
33 ± 25
22 ± 14
\0.05
AST (U/L) Alkaline phosphatase (U/L) c-GT (U/L)
\0.05 0.569
Creatinine (mg/dL)
0.80 ± 0.17
0.77 ± 0.14
\0.05
0.88 ± 0.4
0.80 ± 0.23
Leptin (ng/mL)
61.3 ± 34.3
20.8 ± 15.6
\0.001
33.9 ± 21.4
10.7 ± 5.2
\0.05 \0.01
0.312
Calcium (mg/dL)
9.07 ± 0.42
9.31 ± 0.26
\0.01
8.4 ± 0.5
9.0 ± 0.3
Phosphate (mg/dL)
3.41 ± 0.55
3.93 ± 0.53
\0.001
3.24 ± 0.53
3.52 ± 0.46
25-OH vitamin D (ng/mL)
10.1 ± 4.6
17.2 ± 9.9
\0.001
13.5 ± 8.1
26.3 ± 7.6
Osteocalcin (ng/mL)
3.43 ± 2.19
7.37 ± 4.21
\0.001
4.1 ± 3.0
3.8 ± 2.1
PTH (pg/mL)
85.4 ± 33.3
69.2 ± 24.3
\0.01
117.4 ± 66.3
62.8 ± 21.1
\0.05
ICTP (ng/mL)
6.14 ± 4.39
8.05 ± 3.61
\0.01
3.7 ± 1.6
6.8 ± 3.6
\0.05
0.255 \0.01 0.749
Data are presented as mean ± SD. Differences between groups of subjects were analyzed by two-tailed paired t tests RYGB Roux-en-Y gastric bypass, SG sleeve gastrectomy, WL weight loss, BMI body mass index, EWL excess weight loss, HOMA homeostatic model assessment, QUICKI quantitative insulin sensitivity check index, LDL low-density lipoprotein, HDL high-density lipoprotein, ALT alanine aminotransferase, AST aspartate aminotransferase, c-GT c-glutamyl transferase, PTH parathyroid hormone, ICTP C-terminal telopeptide of type-I collagen, SD standard deviation
significant improvement in glycemia (P \ 0.05) and insulinemia (P \ 0.05), as well as in the HOMA and QUICKI indices (P \ 0.05). Triglyceride concentrations tended to decrease (P = 0.054) and HDL cholesterol levels tended to increase (P = 0.053), while no differences in total and LDL cholesterol were observed. Serum leptin and CRP concentrations decreased significantly (P \ 0.05). Patients who underwent SG had a preoperative mean BMD of 1.155 ± 0.121 g/cm2. Increased levels of calcium (P \ 0.01), vitamin D (P \ 0.01), and ICTP (P \ 0.05)
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and decreased concentrations of PTH (P \ 0.05) and alkaline phosphatase (P \ 0.05) were observed. However, circulating concentrations of OPN were unchanged after SG (Fig. 1). Before SG, circulating OPN levels were positively correlated with plasma ICTP (r = 0.66; P \ 0.05) (Table 2). OPN concentrations were also positively correlated with HOMA index (r = 0.69; P \ 0.05) and negatively correlated with the QUICKI index (r = –0.66; P \ 0.05) after surgery. The change in the circulating levels of OPN after SG showed a negative correlation with
Surg Endosc Fig. 1 Effect of weight loss induced by Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) on osteopontin (OPN) plasma concentrations in obese patients. Data are the mean ± SD of patients who underwent RYGB (n = 40) or SG (n = 11). Statistical differences between pre- and post-surgical values were determined by two-tailed paired Student t tests
Table 2 Correlation of OPN with markers of bone metabolism in obese patients who underwent BS Before surgery
After surgery
r
r
P value
Change in OPN vs. change in bone markers P value
r
P value
RYGB \0.05
Calcium
0.42
0.03
0.861
0.02
0.898
Phosphate
0.09
0.642
0.12
0.512
0.24
0.188
Vitamin D PTH
0.26 0.38
0.122 \0.05
0.31 0.12
0.061 0.492
0.13 -0.17
0.447 0.355
Osteocalcin
0.05
0.802
0.02
0.10
0.582
ICTP
0.15
0.411
0.40
\0.05
0.925
0.31
0.081
Alkaline phosphatase
0.09
0.597
0.50
\0.01
0.21
0.269 0.445
SG Calcium
-0.02
0.951
0.41
0.206
-0.26
Phosphate
0.14
0.693
0.12
0.721
0.21
0.527
Vitamin D
-0.02
0.963
-0.41
0.207
-0.87
\0.001
PTH
0.04
0.915
-0.27
0.417
0.47
0.145
Osteocalcin
0.54
0.064
-0.29
0.385
0.19
0.567
ICTP
0.66
-0.48
0.136
0.69
Alkaline phosphatase
0.43
0.48
0.139
-0.04
\0.05 0.282
\0.05 0.933
Values are Pearson’s correlation coefficients and associated P values OPN osteopontin, BS bariatric surgery, RYGB Roux-en-Y gastric bypass, SG sleeve gastrectomy, PTH parathyroid hormone, ICTP C-terminal telopeptide of type-I collagen
the change in vitamin D (r = –0.87; P \ 0.001) and a positive correlation with the change in ICTP levels (r = 0.69; P \ 0.05).
Discussion Our results show that weight loss in obese patients who underwent RYGB or SG was associated with an improved metabolic and inflammatory profile. Previous studies from our group in patients who underwent weight loss by caloric
restriction showed a decrease in circulating levels of OPN [15]. However, plasma OPN significantly increased after RYGB, which is in agreement with previously reported data [22, 30, 31]. Nevertheless, circulating OPN did not change after SG, showing for the first time that OPN concentrations are affected differently by BS depending on the technique performed. Deficiencies in micronutrients, including some essential minerals and vitamins, are common after BS, despite universal recommendations on vitamin and mineral supplements [32, 38]. However, bone loss after BS may depend
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on the surgical procedure [39, 40]. An association between RYGB and bone loss, partly caused by malabsorption of calcium, phosphate, and vitamin D, has been reported in several studies [41, 42]. In the present study, following European guidelines [32], daily oral vitamin and micronutrient supplements were routinely prescribed to all patients who underwent RYGB to compensate for their possible reduced intake and absorption, but not to those who underwent SG, a restrictive and normalabsorptive procedure. It has been reported that calcium intake may increase OPN expression in mice [43, 44]. In this sense, we observed increased OPN concentrations concomitantly with increased circulating levels of calcium only in the RYGB group, in which a correlation between plasma OPN and calcium levels was found preoperatively but not after surgery. Furthermore, Riedl et al. [30] observed that the increase in OPN after RYGB was correlated positively with markers of bone turnover, such as carboxy-terminal collagen crosslinks, a marker of bone resorption, and osteocalcin, a marker of bone formation. In this regard, we observed an increase in the concentrations of osteocalcin and ICTP, another degradation product of bone collagen, after RYGB, but no decrease in calcium, phosphate, and vitamin D levels, probably due to the oral supplementation after surgery. In addition, plasma OPN levels were positively correlated with alkaline phosphatase and ICTP circulating concentrations after RYGB. Besides, we observed that BMD also tended to decrease in patients who underwent RYGB, which has been confirmed by other groups [41, 42, 45]. Therefore, it seems plausible that the increased concentrations of OPN after RYGB may be related to increased bone resorption, induced in turn by the malabsorptive effects of this surgical technique. In addition to its association with changes in bone remodeling after surgery, the increase in serum levels of OPN after RYGB may be also associated with an increased synthesis of OPN by other organs such as the kidney. In this sense, Canales et al. [46] observed a rise in OPN synthesis within the medullary region of the kidney that was associated with an increased renal glomerular injury in rat after gastric bypass. In patients who underwent SG, the analysis of bone resorption markers also showed an increase in plasma ICTP levels after surgery. In addition, the change in the circulating levels of OPN showed a positive correlation with the change in ICTP concentrations. This increase in bone resorption markers observed in patients who underwent RYGB or SG may be due to reduced gastric juice secretion following surgery. Gastric juice alkalization impairs the absorption of certain nutrients, including calcium [47]. Unfortunately, postoperative bone densitometries in patients who underwent SG were not available because they are not routinely performed within the clinical
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protocol since this surgical technique does not have a malabsorptive component. One possible explanation for the different behaviors of OPN after RYGB and SG has to do with vitamin D changes. The vitamin D concentration increased after both bariatric procedures, with a greater increase after SG. Moreover, the change in vitamin D concentration was negatively correlated with the change in OPN levels only after SG. Thus, it has been recently reported that OPN expression may be reduced by vitamin D [48, 49]. These alterations in nutrient absorption affect bone metabolism, which could explain why plasma OPN concentrations are not decreased in patients who underwent RYGB or SG, contrary to what happens in patients who underwent weight loss by caloric restriction [15]. Interestingly, OPN levels are increased following laparoscopic adjustable gastric banding (LAGB) [30, 50]. This increase could be due to the effect of ghrelin, since contrary to what happens after RYGB and SG, this gastrointestinal hormone is increased following LAGB [51– 53], and several studies have shown that ghrelin stimulates the production of OPN [49, 54], potentially explaining the increased levels of OPN after LAGB. Several studies have previously shown that OPN is involved in obesity-associated inflammation and the development of insulin resistance [22, 55–60]. In the present study, a positive correlation of the circulating OPN levels with insulin and HOMA after RYGB, and a positive correlation with HOMA and a negative correlation with QUICKI after SG were observed. In addition, we found a positive correlation of the change in the circulating concentrations of OPN with the change in the plasma levels of fibrinogen, and a negative correlation of the change in OPN levels with the change in QUICKI after RYGB. These findings suggest that patients who undergo BS with high circulating levels of OPN exhibit higher insulin resistance and a worse inflammatory profile. BS improves the inflammatory profile of obese patients, but certain proinflammatory markers remain unchanged or even increased, as we have observed with circulating OPN levels in the present study. For example, TNF-a and sICAM-1 significantly decrease with caloric restriction, whereas they exhibit no change following BS [19, 20]. Although a cutoff point for the circulating concentrations of OPN have not been previously established, it may be speculated that the increase in OPN concentrations after RYGB reported herein could be associated with a proinflammatory status, hindering the resolution of obesity-associated comorbidities. More research is necessary to understand the different behaviors of OPN after weight loss by caloric restriction or by BS, the time course of changes in OPN concentrations after BS, as well as the differences underlying the different BS approaches.
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In conclusion, our results show that plasma OPN concentrations are increased in patients who underwent RYGB, while no differences were found following SG. The change in OPN levels is related to changes in bone metabolism, suggesting that OPN is involved in the RYGB-induced bone mass loss. More research is needed to better unravel the changes taking place in OPN concentrations following BS.
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Acknowledgments We gratefully acknowledge the valuable collaboration of all the members of the Multidisciplinary Obesity Team (Clı´nica Universidad de Navarra, Pamplona, Spain). This work was supported by grants from the Instituto de Salud Carlos III, Fondo de Investigacio´n Sanitaria (PI11/02681 and PI12/00515) and from the Department of Health (48/2011 and 58/2011) of the Gobierno de Navarra of Spain. CIBER Fisiopatologı´a de la Obesidad y Nutricio´n (CIBERobn) is an initiative of the Instituto de Salud Carlos III, Spain.
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Disclosures Andoni Lancha, Rafael Moncada, Vı´ctor Valentı´, Amaia Rodrı´guez, Victoria Catala´n, Sara Becerril, Beatriz Ramı´rez, Leire Me´ndez-Gime´nez, Marı´a J. Gil, Fernando Rotellar, Secundino Ferna´ndez, Javier Salvador, Gema Fru¨hbeck, and Javier Go´mezAmbrosi have no conflicts of interest or financial ties to disclose.
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and Other Interventional Techniques
Comparative effects of gastric bypass and sleeve gastrectomy on plasma osteopontin concentrations in humans Andoni Lancha • Rafael Moncada • Vı´ctor Valentı´ • Amaia Rodrı´guez • Victoria Catala´n • Sara Becerril • Beatriz Ramı´rez • Leire Me´ndez-Gime´nez Marı´a J. Gil • Fernando Rotellar • Secundino Ferna´ndez • Javier Salvador • Gema Fru¨hbeck • Javier Go´mez-Ambrosi
•
Received: 30 October 2013 / Accepted: 14 February 2014 Ó Springer Science+Business Media New York 2014
Abstract Background Bariatric surgery (BS) has proven to be an effective treatment for morbid obesity. Osteopontin (OPN) is a proinflammatory cytokine involved in the development of obesity. The aim of our study was to determine the effect of weight loss following BS on circulating levels of OPN in humans. Methods Body composition and circulating concentrations of OPN and markers of bone metabolism were determined in obese patients who underwent Roux-en-Y gastric bypass (RYGB; n = 40) or sleeve gastrectomy (SG; n = 11). Results Patients who underwent RYGB or SG showed decreased body weight (P \ 0.001) and body fat percentage (P \ 0.001) as well as lower insulin resistance. However, plasma OPN levels were significantly increased after RYGB (P \ 0.001) but remained unchanged following SG (P = 0.152). Patients who underwent RYGB also showed significantly increased C-terminal telopeptide of type-I collagen (ICTP) (P \ 0.01) and osteocalcin (P \ 0.001) while bone mineral density tended to decrease
(P = 0.086). Moreover, OPN concentrations were positively correlated with the bone resorption marker ICTP after surgery. On the other hand, patients who underwent SG showed significantly increased ICTP levels (P \ 0.05), and the change in OPN was positively correlated with the change in ICTP and negatively with the change in vitamin D after surgery (P \ 0.05). Conclusions RYGB increased circulating OPN levels, while they remained unaltered after SG. The increase in OPN levels after RYGB could be related to the increased bone resorption in relation to its well-known effects on bone of this malabsorptive procedure in comparison to the merely restrictive SG.
A. Lancha A. Rodrı´guez V. Catala´n S. Becerril B. Ramı´rez L. Me´ndez-Gime´nez G. Fru¨hbeck J. Go´mez-Ambrosi (&) Metabolic Research Laboratory, Clı´nica Universidad de Navarra, Irunlarrea 1, 31008 Pamplona, Spain e-mail: [email protected]
V. Valentı´ F. Rotellar Department of Surgery, Clı´nica Universidad de Navarra, 31008 Pamplona, Spain
A. Lancha V. Valentı´ A. Rodrı´guez V. Catala´n S. Becerril B. Ramı´rez L. Me´ndez-Gime´nez M. J. Gil F. Rotellar S. Ferna´ndez J. Salvador G. Fru¨hbeck J. Go´mez-Ambrosi CIBER Fisiopatologı´a de la Obesidad y Nutricio´n (CIBERobn), Instituto de Salud Carlos III, 31008 Pamplona, Spain R. Moncada Department of Anesthesia, Clı´nica Universidad de Navarra, 31008 Pamplona, Spain
Keywords Osteopontin Roux-en-Y gastric bypass Sleeve gastrectomy Bone The prevalence of obesity has increased over recent decades to become a true pandemic [1]. Currently, in Western countries, like the United States, more than 35 % of the
M. J. Gil Department of Biochemistry, Clı´nica Universidad de Navarra, 31008 Pamplona, Spain S. Ferna´ndez Department of Otorhinolaryngology, Clı´nica Universidad de Navarra, 31008 Pamplona, Spain J. Salvador G. Fru¨hbeck Department of Endocrinology & Nutrition, Clı´nica Universidad de Navarra, 31008 Pamplona, Spain
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Surg Endosc
population is obese [2]. Obesity is associated with several pathologies such as hypertension, type 2 diabetes, fatty liver, hyperlipidemia, and cancer, increasing morbidity and mortality [3]. Indeed, weight loss has been associated with an improvement of the obesity-associated comorbidities [4–7]. Bariatric surgery (BS) has been proven to be effective for reducing body weight in obese patients [8, 9]. Roux-enY gastric bypass (RYGB) and sleeve gastrectomy (SG) are now routinely performed surgical techniques for morbidly obese patients [10–12] that improve obesity-associated comorbidities as well as extend life expectancy [13, 14]. Obesity is associated with a chronic state of low-grade chronic inflammation characterized by the abnormal expression of cytokines such as tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), serum amyloid A (SAA), adiponectin, and osteopontin (OPN), among others [15–17]. BS reduces the levels of circulating proinflammatory proteins such as C-reactive protein (CRP), IL-6, IL-18, monocyte chemoattractant protein-1 (MCP-1), and calprotectin, among others, at the same time as increasing the levels of adiponectin (an anti-inflammatory adipokine) [18–21]. BS further reduces the expression of proinflammatory proteins such as TNF-a and CD68 in adipose tissue [18, 22]. These changes may contribute to the improvement in obesityassociated comorbidities after surgery-induced weight loss. OPN was initially identified as a protein of the bone extracellular matrix. However, OPN is expressed in multiple cell types such as osteoclasts, osteoblasts, epithelial cells, and endothelial cells, as well as in cells from the nervous and immune systems [23]. OPN is implicated in bone metabolism, wound healing, immune and inflammatory responses, cancer, kidney physiology, respiratory diseases, and cardiovascular and atherosclerotic processes as well as in the development of diabetes and hepatic steatosis [24–28]. Several studies have demonstrated that OPN is also produced by adipose tissue and that its expression increases in adipose tissue in human obesity [15, 22, 29]. In this sense we have observed that diet-induced weight loss decreased OPN plasma concentrations [15]. However, other studies have reported that plasma OPN levels increase after weight loss due to BS [22, 30, 31]. The aim of the present study was to compare OPN plasma concentrations after RYGB and SG in humans.
Materials and methods Subjects In order to analyze the effect of weight loss achieved by BS on plasma OPN concentrations, 40 obese Caucasian subjects (8 male/32 female) undergoing RYGB and 11 obese
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Caucasian subjects (4 male/7 female) undergoing SG were recruited from patients attending the Department of Endocrinology and Nutrition and the Department of Surgery at the Clı´nica Universidad of Navarra. All the individuals included in the study exhibited a body mass index (BMI) greater than 35 kg/m2. Patients underwent a clinical assessment, including physical examination and body composition analysis, performed by a multidisciplinary team. Patients with signs of infection were excluded. All subjects were nonsmokers. Obese patients were not taking statins and diabetic or antihypertensive medication. Following European guidelines, daily oral vitamin and micronutrient supplements were routinely prescribed to all patients who underwent RYGB, to compensate for their possible reduced intake and absorption, but not to those who underwent SG, given that this is a restrictive technique and not a malabsorptive procedure [32]. The interventions were performed via a laparoscopic approach. The experimental design was approved, from an ethical and scientific standpoint, by the hospital’s Ethical Committee responsible for research. Volunteers signed informed consent to participate in the study. Anthropometric measurements Body weight was measured with a digital scale to the nearest 0.1 kg, and height was measured to the nearest 0.1 cm with a Holstein stadiometer (Holstein Ltd., Crimes, UK). BMI was calculated as weight in kg divided by the square of height in meters. Body fat was estimated by airdisplacement plethysmography (Bod-PodÒ, Life Measurements, Concord, CA, USA) as previously described [33, 34]. Excess weight loss (EWL) was calculated as weight loss divided by the excess weight. Analytical procedures Blood samples were collected after an overnight fast in the morning in order to avoid potential confounding influences due to hormonal rhythmicity. Plasma glucose was analyzed using an automated analyzer (Roche/Hitachi Modular P800, Basel, Switzerland) as previously described [35]. Insulin was measured by means of an enzyme-amplified chemiluminescence assay (Immulite, Diagnostic Products Corp., Los Angeles, CA, USA). Insulin resistance was determined by means of the homeostatic model assessment (HOMA) index expressed as glucose (mmol/L) 9 insulin (lU/mL)/22.5 [36]. Insulin sensitivity was calculated by using the quantitative insulin sensitivity check index (QUICKI) [37]. This index is a simple accurate method for assessing insulin sensitivity in humans and is defined as 1/ (log[insulin0] ? log[glucose0]). Total cholesterol and triglyceride concentrations were determined by enzymatic
Surg Endosc
spectrophotometric methods (Roche, Basel, Switzerland). High-density-lipoprotein (HDL) cholesterol was quantified by a colorimetric method in a Beckman Synchron CX analyzer (Beckman Instruments, Ltd., Bucks, UK). Lowdensity-lipoprotein (LDL) cholesterol was calculated using the Friedewald formula [35]. Calcium and phosphate were analyzed by colorimetric methods. Uric acid, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, c-glutamyl transferase (c-GT), and creatinine were measured by enzymatic tests (Roche) in an automated analyzer (Roche/Hitachi Modular P800). Fibrinogen concentrations were determined according to the method of Clauss using a commercially available kit (Hemoliance, Instrumentation Laboratory, Barcelona, Spain). Measurement of von Willebrand factor antigen was performed by a microlatex immunoassay (Diagnostica Stago, Inc., Parsippany, NJ, USA). A standard curve was prepared with a universal reference (NISBC 91/666) and the results were expressed as percentage of the standard. Intra- and interassay coefficients of variation (CV) were 4.0 and 8.0 %, respectively. Parathyroid hormone (PTH) and osteocalcin were analyzed by chemiluminescent methods with an Immulite 2500 (Siemens AG, Erlagen, Germany). High-sensitivity CRP was measured using the Tina-quant CRP (Latex) ultrasensitive assay (Roche). Leptin (Linco Research, Inc., St. Charles, MO, USA) was quantified by a double-antibody RIA method. Intra- and interassay CV were 5.0 and 4.5 %, respectively. C-terminal telopeptide of type-I collagen (ICTP) was measured by RIA (Orion Diagnostica, Espoo, Finland). Intra- and interassay CV were 4.8 and 5.6 %, respectively. 25-Hydroxyvitamin D was quantified by ELISA (Immundiagnostik AG, Bensheim, Germany), with intra- and interassay CV of 10.7 and 11.8 %, respectively. OPN was determined by ELISA (R&D Systems Inc., Minneapolis, MN, USA) with intra- and interassay CV of 3.2 and 5.9 %, respectively. Bone mineral density (BMD) measurements BMD was measured at the lumbar spine (L2–L4) by dualenergy X-ray absorptiometry (DEXA) using a Lunar iDXA (GE Healthcare Lunar, Madison, WI, USA) as previously described [15]. Statistical analysis Data are presented as mean ± standard deviation (SD). Sample size was estimated using the program PS Power and Sample Size Calculations (edition 2.1.30). The effect of weight loss after RYGB was analyzed by two-tailed paired t tests. Correlations between two variables were assessed by Pearson’s correlation coefficient. The
calculations were performed using the SPSS for Windows ver. 15.0.1 (SPSS, Inc., Chicago, IL, USA). A P value less than 0.05 was considered statistically significant.
Results Effect of weight loss by RYGB on plasma OPN concentrations in obese patients After an average of 15 months following RYGB, patients showed a significant (P \ 0.001) decrease in body weight, BMI, and body fat percentage, as well as a significant improvement in glycemia (P \ 0.001), insulinemia (P \ 0.001), and HOMA and QUICKI indices (P \ 0.001) (Table 1). Triglyceride (P \ 0.001) as well as total (P \ 0.001) and LDL cholesterol (P \ 0.001) concentrations were significantly reduced, while HDL cholesterol levels were increased (P \ 0.001). Leptin and CRP concentrations were also notably improved (P \ 0.001). An increase in the levels of calcium (P \ 0.01), phosphate (P \ 0.001), vitamin D (P \ 0.001), osteocalcin (P \ 0.001), and ICTP (P \ 0.001) as well as a decrease in the concentrations of PTH (P \ 0.01) were observed (Table 1). BMD tended to decrease from 1.052 ± 0.126 to 1.026 ± 0.161 g/cm2 after RYGB, although the differences did not reach statistical significance (P = 0.086). Circulating OPN concentrations were significantly increased (P \ 0.001) after RYGB (Fig. 1). Before RYGB, circulating OPN concentrations were positively correlated with plasma PTH (r = 0.38; P \ 0.05) and calcium (r = 0.42; P \ 0.05) levels (Table 2). Interestingly, circulating OPN levels were positively correlated with the marker of bone resorption ICTP (r = 0.40; P \ 0.05), and with alkaline phosphatase (r = 0.50; P \ 0.01) concentrations after surgery. The change in the circulating levels of OPN after surgery also showed a trend toward a positive correlation with the change in ICTP levels (r = 0.31; P = 0.081). Moreover, OPN concentrations were positively correlated with insulin levels (r = 0.42; P \ 0.05) and HOMA index (r = 0.36; P \ 0.05) after surgery. The change in the circulating levels of OPN after the operation showed a positive correlation with the change in plasma fibrinogen (r = 0.49; P \ 0.01) and CRP (r = 0.51; P \ 0.05) levels and a negative correlation with the change in the QUICKI index (r = -0.41; P \ 0.05). Effect of weight loss by SG on plasma OPN concentrations in obese patients One year after the operation, patients who underwent SG showed a significant decrease (P \ 0.001) in body weight, BMI, and body fat percentage (Table 1). There was also a
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Surg Endosc Table 1 Effect of surgically induced weight loss in obese patients RYGB Before WL Sex (male/female)
8/32
SG After WL –
Age (years)
38.7 ± 13.5
40.4 ± 13.4
Body weight (kg)
123 ± 30
80 ± 19
2
P
Before WL – –
\0.001
After WL
4/7
–
44.3 ± 10.5
45.5 ± 10.3
113 ± 20
80 ± 20
P – – \0.001
BMI (kg/m )
45.2 ± 7.9
29.5 ± 5.2
\0.001
40.4 ± 6.1
29.2 ± 5.7
\0.001
Body fat (%)
51.7 ± 6.2
33.0 ± 10.3
\0.001
47.6 ± 6.8
35.1 ± 9.1
\0.001
EWL (%) Waist circumference (cm) Waist-to-hip ratio Glucose (mmol/L) Insulin (pmol/L)
– 120 ± 16 0.90 ± 0.08
72.3 ± 17.9 92 ± 13 0.86 ± 0.07
– \0.001 \0.001
– 125 ± 13 1.02 ± 0.09
64.8 ± 25.4 100 ± 16 0.95 ± 0.11
– \0.001 \0.05
5.38 ± 0.97
4.56 ± 0.51
\0.001
7.74 ± 4.01
5.46 ± 1.38
\0.05
120.3 ± 68.8
50.2 ± 24.5
\0.001
229.1 ± 251.7
64.5 ± 54.8
\0.05
HOMA
4.3 ± 2.6
1.3 ± 0.8
\0.001
13.1 ± 7.5
2.7 ± 2.5
\0.05
QUICKI
0.319 ± 0.026
0.372 ± 0.037
\0.001
0.294 ± 0.054
0.362 ± 0.062
\0.05
1.32 ± 0.46
0.90 ± 0.29
\0.001
1.72 ± 1.18
1.24 ± 0.60
Triglycerides (mmol/L)
0.054
Total cholesterol (mmol/L)
5.25 ± 1.01
4.01 ± 0.91
\0.001
4.75 ± 0.62
4.94 ± 0.61
0.357
LDL-cholesterol (mmol/L)
3.38 ± 0.81
2.29 ± 0.62
\0.001
2.82 ± 0.53
2.94 ± 0.70
0.457
HDL-cholesterol (mmol/L)
1.06 ± 0.22
1.31 ± 0.49
\0.001
1.13 ± 0.26
1.44 ± 0.47
0.053
5.7 ± 1.5
4.3 ± 1.0
\0.001
4.9 ± 1.3
4.7 ± 1.4
0.541
Uric acid (mg/dL) Fibrinogen (mg/dL)
323 ± 88
321 ± 71
0.484
352 ± 86
311 ± 80
0.206
von Willebrand factor (%)
125 ± 61
121 ± 42
0.192
98 ± 41
76 ± 29
0.509
C-reactive protein (mg/L)
9.6 ± 6.1
2.3 ± 3.3
\0.001
6.3 ± 3.4
1.5 ± 1.1
ALT (U/L)
26 ± 18
20 ± 9
0.061
23 ± 15
14 ± 4
15 ± 7 106 ± 26
15 ± 4 110 ± 31
0.896 0.586
15 ± 10 79 ± 31
13 ± 2 53 ± 15
0.132 \0.05
20 ± 10
10 ± 5
\0.001
33 ± 25
22 ± 14
\0.05
AST (U/L) Alkaline phosphatase (U/L) c-GT (U/L)
\0.05 0.569
Creatinine (mg/dL)
0.80 ± 0.17
0.77 ± 0.14
\0.05
0.88 ± 0.4
0.80 ± 0.23
Leptin (ng/mL)
61.3 ± 34.3
20.8 ± 15.6
\0.001
33.9 ± 21.4
10.7 ± 5.2
\0.05 \0.01
0.312
Calcium (mg/dL)
9.07 ± 0.42
9.31 ± 0.26
\0.01
8.4 ± 0.5
9.0 ± 0.3
Phosphate (mg/dL)
3.41 ± 0.55
3.93 ± 0.53
\0.001
3.24 ± 0.53
3.52 ± 0.46
25-OH vitamin D (ng/mL)
10.1 ± 4.6
17.2 ± 9.9
\0.001
13.5 ± 8.1
26.3 ± 7.6
Osteocalcin (ng/mL)
3.43 ± 2.19
7.37 ± 4.21
\0.001
4.1 ± 3.0
3.8 ± 2.1
PTH (pg/mL)
85.4 ± 33.3
69.2 ± 24.3
\0.01
117.4 ± 66.3
62.8 ± 21.1
\0.05
ICTP (ng/mL)
6.14 ± 4.39
8.05 ± 3.61
\0.01
3.7 ± 1.6
6.8 ± 3.6
\0.05
0.255 \0.01 0.749
Data are presented as mean ± SD. Differences between groups of subjects were analyzed by two-tailed paired t tests RYGB Roux-en-Y gastric bypass, SG sleeve gastrectomy, WL weight loss, BMI body mass index, EWL excess weight loss, HOMA homeostatic model assessment, QUICKI quantitative insulin sensitivity check index, LDL low-density lipoprotein, HDL high-density lipoprotein, ALT alanine aminotransferase, AST aspartate aminotransferase, c-GT c-glutamyl transferase, PTH parathyroid hormone, ICTP C-terminal telopeptide of type-I collagen, SD standard deviation
significant improvement in glycemia (P \ 0.05) and insulinemia (P \ 0.05), as well as in the HOMA and QUICKI indices (P \ 0.05). Triglyceride concentrations tended to decrease (P = 0.054) and HDL cholesterol levels tended to increase (P = 0.053), while no differences in total and LDL cholesterol were observed. Serum leptin and CRP concentrations decreased significantly (P \ 0.05). Patients who underwent SG had a preoperative mean BMD of 1.155 ± 0.121 g/cm2. Increased levels of calcium (P \ 0.01), vitamin D (P \ 0.01), and ICTP (P \ 0.05)
123
and decreased concentrations of PTH (P \ 0.05) and alkaline phosphatase (P \ 0.05) were observed. However, circulating concentrations of OPN were unchanged after SG (Fig. 1). Before SG, circulating OPN levels were positively correlated with plasma ICTP (r = 0.66; P \ 0.05) (Table 2). OPN concentrations were also positively correlated with HOMA index (r = 0.69; P \ 0.05) and negatively correlated with the QUICKI index (r = –0.66; P \ 0.05) after surgery. The change in the circulating levels of OPN after SG showed a negative correlation with
Surg Endosc Fig. 1 Effect of weight loss induced by Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) on osteopontin (OPN) plasma concentrations in obese patients. Data are the mean ± SD of patients who underwent RYGB (n = 40) or SG (n = 11). Statistical differences between pre- and post-surgical values were determined by two-tailed paired Student t tests
Table 2 Correlation of OPN with markers of bone metabolism in obese patients who underwent BS Before surgery
After surgery
r
r
P value
Change in OPN vs. change in bone markers P value
r
P value
RYGB \0.05
Calcium
0.42
0.03
0.861
0.02
0.898
Phosphate
0.09
0.642
0.12
0.512
0.24
0.188
Vitamin D PTH
0.26 0.38
0.122 \0.05
0.31 0.12
0.061 0.492
0.13 -0.17
0.447 0.355
Osteocalcin
0.05
0.802
0.02
0.10
0.582
ICTP
0.15
0.411
0.40
\0.05
0.925
0.31
0.081
Alkaline phosphatase
0.09
0.597
0.50
\0.01
0.21
0.269 0.445
SG Calcium
-0.02
0.951
0.41
0.206
-0.26
Phosphate
0.14
0.693
0.12
0.721
0.21
0.527
Vitamin D
-0.02
0.963
-0.41
0.207
-0.87
\0.001
PTH
0.04
0.915
-0.27
0.417
0.47
0.145
Osteocalcin
0.54
0.064
-0.29
0.385
0.19
0.567
ICTP
0.66
-0.48
0.136
0.69
Alkaline phosphatase
0.43
0.48
0.139
-0.04
\0.05 0.282
\0.05 0.933
Values are Pearson’s correlation coefficients and associated P values OPN osteopontin, BS bariatric surgery, RYGB Roux-en-Y gastric bypass, SG sleeve gastrectomy, PTH parathyroid hormone, ICTP C-terminal telopeptide of type-I collagen
the change in vitamin D (r = –0.87; P \ 0.001) and a positive correlation with the change in ICTP levels (r = 0.69; P \ 0.05).
Discussion Our results show that weight loss in obese patients who underwent RYGB or SG was associated with an improved metabolic and inflammatory profile. Previous studies from our group in patients who underwent weight loss by caloric
restriction showed a decrease in circulating levels of OPN [15]. However, plasma OPN significantly increased after RYGB, which is in agreement with previously reported data [22, 30, 31]. Nevertheless, circulating OPN did not change after SG, showing for the first time that OPN concentrations are affected differently by BS depending on the technique performed. Deficiencies in micronutrients, including some essential minerals and vitamins, are common after BS, despite universal recommendations on vitamin and mineral supplements [32, 38]. However, bone loss after BS may depend
123
Surg Endosc
on the surgical procedure [39, 40]. An association between RYGB and bone loss, partly caused by malabsorption of calcium, phosphate, and vitamin D, has been reported in several studies [41, 42]. In the present study, following European guidelines [32], daily oral vitamin and micronutrient supplements were routinely prescribed to all patients who underwent RYGB to compensate for their possible reduced intake and absorption, but not to those who underwent SG, a restrictive and normalabsorptive procedure. It has been reported that calcium intake may increase OPN expression in mice [43, 44]. In this sense, we observed increased OPN concentrations concomitantly with increased circulating levels of calcium only in the RYGB group, in which a correlation between plasma OPN and calcium levels was found preoperatively but not after surgery. Furthermore, Riedl et al. [30] observed that the increase in OPN after RYGB was correlated positively with markers of bone turnover, such as carboxy-terminal collagen crosslinks, a marker of bone resorption, and osteocalcin, a marker of bone formation. In this regard, we observed an increase in the concentrations of osteocalcin and ICTP, another degradation product of bone collagen, after RYGB, but no decrease in calcium, phosphate, and vitamin D levels, probably due to the oral supplementation after surgery. In addition, plasma OPN levels were positively correlated with alkaline phosphatase and ICTP circulating concentrations after RYGB. Besides, we observed that BMD also tended to decrease in patients who underwent RYGB, which has been confirmed by other groups [41, 42, 45]. Therefore, it seems plausible that the increased concentrations of OPN after RYGB may be related to increased bone resorption, induced in turn by the malabsorptive effects of this surgical technique. In addition to its association with changes in bone remodeling after surgery, the increase in serum levels of OPN after RYGB may be also associated with an increased synthesis of OPN by other organs such as the kidney. In this sense, Canales et al. [46] observed a rise in OPN synthesis within the medullary region of the kidney that was associated with an increased renal glomerular injury in rat after gastric bypass. In patients who underwent SG, the analysis of bone resorption markers also showed an increase in plasma ICTP levels after surgery. In addition, the change in the circulating levels of OPN showed a positive correlation with the change in ICTP concentrations. This increase in bone resorption markers observed in patients who underwent RYGB or SG may be due to reduced gastric juice secretion following surgery. Gastric juice alkalization impairs the absorption of certain nutrients, including calcium [47]. Unfortunately, postoperative bone densitometries in patients who underwent SG were not available because they are not routinely performed within the clinical
123
protocol since this surgical technique does not have a malabsorptive component. One possible explanation for the different behaviors of OPN after RYGB and SG has to do with vitamin D changes. The vitamin D concentration increased after both bariatric procedures, with a greater increase after SG. Moreover, the change in vitamin D concentration was negatively correlated with the change in OPN levels only after SG. Thus, it has been recently reported that OPN expression may be reduced by vitamin D [48, 49]. These alterations in nutrient absorption affect bone metabolism, which could explain why plasma OPN concentrations are not decreased in patients who underwent RYGB or SG, contrary to what happens in patients who underwent weight loss by caloric restriction [15]. Interestingly, OPN levels are increased following laparoscopic adjustable gastric banding (LAGB) [30, 50]. This increase could be due to the effect of ghrelin, since contrary to what happens after RYGB and SG, this gastrointestinal hormone is increased following LAGB [51– 53], and several studies have shown that ghrelin stimulates the production of OPN [49, 54], potentially explaining the increased levels of OPN after LAGB. Several studies have previously shown that OPN is involved in obesity-associated inflammation and the development of insulin resistance [22, 55–60]. In the present study, a positive correlation of the circulating OPN levels with insulin and HOMA after RYGB, and a positive correlation with HOMA and a negative correlation with QUICKI after SG were observed. In addition, we found a positive correlation of the change in the circulating concentrations of OPN with the change in the plasma levels of fibrinogen, and a negative correlation of the change in OPN levels with the change in QUICKI after RYGB. These findings suggest that patients who undergo BS with high circulating levels of OPN exhibit higher insulin resistance and a worse inflammatory profile. BS improves the inflammatory profile of obese patients, but certain proinflammatory markers remain unchanged or even increased, as we have observed with circulating OPN levels in the present study. For example, TNF-a and sICAM-1 significantly decrease with caloric restriction, whereas they exhibit no change following BS [19, 20]. Although a cutoff point for the circulating concentrations of OPN have not been previously established, it may be speculated that the increase in OPN concentrations after RYGB reported herein could be associated with a proinflammatory status, hindering the resolution of obesity-associated comorbidities. More research is necessary to understand the different behaviors of OPN after weight loss by caloric restriction or by BS, the time course of changes in OPN concentrations after BS, as well as the differences underlying the different BS approaches.
Surg Endosc
In conclusion, our results show that plasma OPN concentrations are increased in patients who underwent RYGB, while no differences were found following SG. The change in OPN levels is related to changes in bone metabolism, suggesting that OPN is involved in the RYGB-induced bone mass loss. More research is needed to better unravel the changes taking place in OPN concentrations following BS.
10.
11.
Acknowledgments We gratefully acknowledge the valuable collaboration of all the members of the Multidisciplinary Obesity Team (Clı´nica Universidad de Navarra, Pamplona, Spain). This work was supported by grants from the Instituto de Salud Carlos III, Fondo de Investigacio´n Sanitaria (PI11/02681 and PI12/00515) and from the Department of Health (48/2011 and 58/2011) of the Gobierno de Navarra of Spain. CIBER Fisiopatologı´a de la Obesidad y Nutricio´n (CIBERobn) is an initiative of the Instituto de Salud Carlos III, Spain.
12.
Disclosures Andoni Lancha, Rafael Moncada, Vı´ctor Valentı´, Amaia Rodrı´guez, Victoria Catala´n, Sara Becerril, Beatriz Ramı´rez, Leire Me´ndez-Gime´nez, Marı´a J. Gil, Fernando Rotellar, Secundino Ferna´ndez, Javier Salvador, Gema Fru¨hbeck, and Javier Go´mezAmbrosi have no conflicts of interest or financial ties to disclose.
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13.
15.
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