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Keywords:

  • adiponectin;
  • bariatric surgery;
  • biliopancreatic diversion;
  • weight loss;
  • light-molecular weight adiponectin

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Objective: Our objective was to test the effect of biliopancreatic diversion (BDP) in adiponectin multimerization. Adiponectin, the major protein secreted by adipose tissue, circulates in plasma in different isoforms. The most clinically relevant oligomers are high-molecular weight (HMW) multimers and low-molecular weight (LMW) trimers. Contrasting data on the effect of weight loss on adiponectin isoforms have been reported.

Research Methods and Procedures: We measured total plasma adiponectin and HMW and LMW adiponectin oligomers (by Western blot analysis) before and 1 month after BPD, in 18 severely obese subjects.

Results: One month after BPD, body weight decreased ∼11%. Total adiponectin showed significant increase after BPD. In addition, we found a significant increase in HMW (percentage) adiponectin oligomers. We found a significant inverse correlation between HMW (percentage) and BMI before and after BPD. Homeostasis model of assessment-insulin resistance decreased significantly after the BPD, without any significant correlation with total serum adiponectin and adiponectin oligomers.

Discussion: A moderate weight loss after BPD increases total and HMW adiponectin oligomers. The significant correlation between BMI and HMW (percentage) adiponectin oligomers but not between BMI and total adiponectin might indicate a role of body fat mass in regulation of adiponectin multimerization. These data suggest that HMW oligomers represent a very sensitive parameter to short-term BMI changes after BPD.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Adiponectin, the most abundant adipocytokine produced by adipose tissue, has been proposed as a link among obesity, insulin resistance (IR),1 and cardiovascular diseases (1,2). Adiponectin circulates in plasma in multimeric isoforms, and the most clinically relevant are low molecular weight (LMW) and high molecular weight (HMW). The HMW adiponectin seems to represent the more active oligomeric form, and it is thought to have enhanced biological activity in insulin action compared with LMW adiponectin (3). The regulation of the multimerization process and the biological role of adiponectin isoforms are not yet completely understood. Recently, it has been reported that there is an increase in HMW adiponectin in obese subjects after diet-induced weight loss (4); however, contrasting results have been reported (5).

Bariatric surgery is a well-recognized method for the treatment of severe obesity, and in most patients, the surgically induced weight loss increases adiponectin (6). The effect of bariatric surgery on circulating adiponectin isoforms is still unexplored. Hence, in this study, total adiponectin concentration and its circulating oligomers percentage before and after biliopancreatic diversion (BPD) (7) were measured. To evaluate the effect of moderate weight loss, the evaluation was made very shortly after BPD, when body weight (BW) of subjects was still in the obese range.

Research Methods and Procedures

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

The study was carried out in 18 obese non-diabetic patients (7 men and 11 women) eligible for BPD, with a mean BW of 126.2 kg (range, 101 to 160) and mean BMI values of 45.0 kg/m2 (range, 36.7–58). All patients gave written informed consent. The patients were evaluated preoperatively and at 1 month after BPD; a blood sample was drawn at 8 am after an overnight fast; BW and stature were measured to the nearest 0.1 kg and 0.1 cm, respectively. After separation, serum samples were stored at −20 °C until analysis.

Serum adiponectin, glucose, and insulin concentrations were measured respectively by commercial radioimmunoassay (DRG Instruments GmbH, Marburg/Lahn, Germany), enzymatic method (Randox Laboratories Ltd., Crumlin, County Antrim, United Kingdom), and sandwich enzyme immunoassay (Beckman Coulter, Fullerton, CA). Total cholesterol, high-density lipoprotein (HDL)-cholesterol, and triglycerides were determined on a Hitachi analyzer (Roche Diagnostics, Mannheim, Germany). Low-density lipoproteincholesterol was calculated by the Friedewald equation. Insulin sensitivity was estimated according to the homeostasis model of assessment (HOMA)-IR index. All measurements were made in duplicate in the same batch.

Serum was subjected to non-reducing non-denaturing sodium dodecyl sulfate-polyacrylamide gel electrophoresis (4). Bands corresponding to HMW and LMW were quantified by densitometry on the same membrane using NIH Image software. HMW (percentage) in this manuscript represents HMW/(HMW + LMW) × 100. The differences between pre- and post-BPD values were assessed by Wilcoxon signed rank test, and linear regression was employed to evaluate the relationship between data.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Table 1 shows anthropometric and metabolic characteristics of subjects before and after BPD. One month after BPD, there was a significant reduction both in BW and in BMI, serum insulin, and HOMA-IR. Also, total cholesterol and HDL decreased significantly, whereas low-density lipoprotein and triglyceride reduction was not significant.

Table 1.  Patients characteristics before and 1 month after BPD
 Before BPDAfter BPDp value
  1. BW, body weight; HMW(%), percentage of high molecular weight adiponectin. Data are means ± standard deviation. The differences between pre- and post-BPD values were assessed by Wilcoxon signed rank test.

BW (kg)126.2 ± 15.9113.3 ± 15.90.0002
BMI (kg/m2)45.0 ± 5.739.6 ± 5.10.0002
Glucose (mM/L)6.6 ± 3.25.4 ± 1.40.03
Insulin (μU/mL)20.1 ± 10.511.0 ± 6.40.002
HOMA-IR6.3 ± 5.02.6 ± 1.60.001
Total adiponectin (μg/mL)8.5 ± 3.710.2 ± 4.50.01
Total cholesterol (mM/L)5.2 ± 1.13.7 ± 0.70.002
HDL (mM/L)1.26 ± 0.330.92 ± 0.310.004
LDL (mM/L)3.0 ± 1.12.0 ± 0.60.11
Triglicerides (mM/L)2.3 ± 2.51.8 ± 1.00.70
HMW(%)39.0 ± 12.549.0 ± 12.40.002

Total adiponectin showed a significant increase (8.5 ± 3.7 vs. 10.2 ± 4.5, p < 0.01). Moreover, significant changes in adiponectin oligomers composition were observed. The HMW (percentage) increased from 39 ± 12.5 to 49 ± 12.4 (p < 0.002), and, conversely, LMW (percentage) decreased from 61 ± 12.5 to 51 ± 12.3 (p < 0.01) (Figure 1).

image

Figure 1. Adiponectin oligomer composition before and after BPD. Two microliters of each serum was subjected to 8% sodium dodecyl sulfate-polyacrylamide gel electrophoresis under non-reducing, non-denaturing conditions. Specific adiponectin oligomers were found at >300 kDa, which represent HMW complex, and at ∼70 kDa, which represent LMW trimers. * p < 0.01.

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We observed a sexual dimorphism in total adiponectin before and after BPD (women, 9.4 ± 4.1 vs. 11.6 ± 4.9; men, 7.1 ± 2.4 vs. 8.1 ± 2.8). This difference was not only limited to the absolute amount of adiponectin but was also present in the percentage of HMW oligomeric forms (women, 40.3 ± 10.2 vs. 50.3 ± 12.8; men, 36.9 ± 16.1 vs. 48.1 ± 12.4).

We did not find any correlation among serum adiponectin concentrations, adiponectin oligomers, and parameters of glucose metabolism. We observed a significant correlation between total adiponectin and HDL-cholesterol before BPD (r = 0.58, p = 0.03). This correlation lost statistical significance after the surgery.

Although total adiponectin did not show any relationship with BW and BMI, a negative correlation between HMW (percentage) and BMI before BPD (r = −0.486, p < 0.05) and after BPD (r = −0.459, p < 0.05) was observed. The level of significance increased when all values were analyzed together (Figure 2).

image

Figure 2. Correlation analysis between HMW (percentage) adiponectin and BMI before (•) and after (○) BPD. The figure shows a strong negative relationship between HMW (percentage) and BMI values.

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

The main result of this study is that a moderate weight loss at a short term after BPD affects adiponectin oligomer composition, resulting in a relative increase in HMW forms. The data herein show that a loss of 11% of the initial BW induced by BPD increases adiponectin HMW isoform. An increase in total adiponectin concentration was also present, and it was statistically significant. Also for total adiponectin (8), a sexual dimorphism was present in HMW adiponectin before and after BPD. However, gender did not influence the effect of BPD.

Previous studies concerning the effect of diet-induced weight loss on adiponectin isoforms reported contrasting data (4,5,9). The mechanism by which weight reduction could affect adiponectin oligomerization is unknown. Because treatment with thiazolidinedione is the only way known to increase HMW adiponectin (3,5), it is possible that the negative energy balance associated with weight loss regulates adiponectin production by peroxisome proliferator-activated receptor-γ activation (10). Specific dietary manipulations (fatty meal or oral glucose) probably do not play a role in secretion of adiponectin and its oligomers, as showed by Peake et al. (11). It is possible that fat loss by itself affects adiponectin oligomers; in fact, the same weight loss induced by different ways (BPD and diet) gave very similar results. Therefore, body mass could have a major role in regulating adiponectin oligomer composition and in signaling the energy balance status. Supporting this hypothesis, we observed a strong correlation between BMI and HMW (percentage) adiponectin.

Previous investigations demonstrated that weight normalization after BPD and gastric bypass is associated with an increase of serum circulating adiponectin concentration (6). This study shows changes in adiponectin isoform composition already in the first post-operative months, when patients are still obese. However, HMW (percentage) adiponectin, in contrast to the levels of total adiponectin, is significantly correlated to adipose tissue mass. The lack of a correlation between total adiponectin and BMI in obese patients was also confirmed by other groups (12). It is possible to speculate that adiponectin and its multimeric forms could be influenced by independent mechanisms of regulation underlying the importance of adipocyte biology.

It is well known that the metabolic benefits of BPD are already evident in the early post-operative periods, when BW is still in the obese range (13). Confirming previous data, HOMA-IR normalized 1 month after BPD. HMW adiponectin seems to be the more metabolically active isoform (3); therefore, the post-operative increase of HMW adiponectin leads to the hypothesis that it may play a substantial role in the post-BPD recovery of insulin activity. To test this hypothesis, we analyzed the relationship of HOMA-IR and HMW adiponectin oligomers, but we did not find any correlation.

As previously reported, plasma HDL and total adiponectin showed a positive correlation (14). We confirmed these data before the surgery. After BPD, the lack of correlation between total adiponectin and HMW could be due to confounding factors such as the reduced intestinal cholesterol absorption and/or recent surgical stress that might reduce HDL concentration.

The role of other factors, such as lipid deprivation or activation of intestinal insulin-sensitizing agents, has to be considered in post-BPD insulin sensitivity rescue.

In conclusion, this study demonstrates that HMW adiponectin oligomers are increased 1 month after BPD. The correlation between BMI and HMW adiponectin oligomers might indicate a role of body fat mass in regulation of adiponectin multimerization.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

We thank Maria Rosa Dagnino for skillful administrative assistance and Dr. Theodore Ciaraldi for helpful suggestions. This work was supported, in part, by grants from the Ministero dell'Istruzione, dell'Università e della Ricerca, the Fondo per gli Investimenti della Ricerca di Base, the Fondazione CARIGE, and the University of Genova.

Footnotes
  • 1

    Nonstandard abbreviations: IR, insulin resistance; LMW, low molecular weight; HMW, high molecular weight; BPD, biliopancreatic diversion; BW, body weight; HDL, high-density lipoprotein; HOMA, homeostasis model of assessment.

  • The costs of publication of this article were defrayed, in part, by the payment of page charges. This article must, therefore, be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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  2. Abstract
  3. Introduction
  4. Research Methods and Procedures
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
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