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Variation in blood levels of hormones in obese patients following weight reduction induced by endoscopic and surgical bariatric therapies
Cytokine 77 (2016) 56–62
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Variation in blood levels of hormones in obese patients following weight reduction induced by endoscopic and surgical bariatric therapies Eugeniusz Wroblewski a, Agnieszka Swidnicka-Siergiejko a,⇑, Hady Razak Hady b, Magdalena Luba b, Marzena Konopko a, Krzysztof Kurek a, Jacek Dadan b, Andrzej Dabrowski a a b
Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, Poland 1st Clinical Department of General and Endocrine Surgery, Medical University of Bialystok, Poland
a r t i c l e
i n f o
Article history: Received 31 May 2015 Received in revised form 2 October 2015 Accepted 26 October 2015 Available online 2 November 2015 Keywords: Obesity Adipokines Weight loss Gastric balloon Bariatric surgery
a b s t r a c t Background: Beneficial clinical effects of weight reduction following bariatric therapies is not fully understood and maybe related to the complex interactions between leptin, adiponectin, visfatin, omentin, and ghrelin. The aim of study was to investigate their timeline changes associated with weight reduction and their profile in relation to the type of treatment and its efficacy. Methods: Circulating hormones levels were analyzed before and after endoscopic and surgical procedures in 67 obese patients and compared to non-obese healthy controls. Results: Obese patients had higher leptin levels and lower levels of adiponectin, visfatin, omentin, and ghrelin than non-obese controls. During the consecutive follow-up visits after treatment, there was a gradual decrease in leptin levels and an increase in adiponectin levels to the levels observed in nonobese. At 50–54 weeks, the ghrelin levels were lower and the levels of adiponectin and visfatin, but not omentin, were higher compared to their baseline values. BMI correlated with ghrelin and leptin levels. The percentage of total weight loss correlated positively with adiponectin levels and negatively with leptin levels. Patients with adequate weight loss had a significantly lower leptin concentration than those with treatment failure. There were timeline variations in hormone levels between endoscopic and bariatric therapies, however there were no significant differences in the median their concentration at 50–54 weeks after therapy. Conclusion: Our study supports observations that weight loss itself, rather than the procedure type, is responsible for hormonal variation. The leptin levels reflect the best the body weight changes after bariatric therapies. Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction Obesity is among the fastest growing diseases worldwide that increases the risk of the numbers of complications including cardiovascular diseases, diabetes mellitus and cancers. The mechanism how obesity contributes to complications is more complex and includes gastrointestinal hormones, adipokines, insulin and
Abbreviations: BIB, bioenterics intragastric balloon; LAGBl, aparoscopic adjustable gastric banding; LSG, laparoscopic sleeve gastrectomy; %IBW, the percentage of initial body weight; %EWL, the percentage of excess weight loss; %TWL, the percentage of total weight loss. ⇑ Corresponding author at: Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, Ul. M. Sklodowskiej-Curie 24a, 15-276 Bialystok, Poland. E-mail address: [email protected] (A. Swidnicka-Siergiejko). http://dx.doi.org/10.1016/j.cyto.2015.10.013 1043-4666/Ó 2015 Elsevier Ltd. All rights reserved.
insulin-like growth factor signaling pathways, inflammation, immune responses, gut-brain axis, hypothalamic nervous system, and gut microbiota. Dysregulation in these systems associated with fat accumulation may lead to chronic inflammation and then to cancer development [1,2]. Among adipokines expressed by white adipose tissue, adiponectin has a protective role as it regulates insulin sensitivity, has anti-inflammatory, and antiatherogenic properties [3,4]. Leptin regulates energy hemostasis by controlling satiety and body weight, plays a role in angiogenesis and it is a key proinflammatory factor modulating the immune system [5,6]. Recent data suggests that novel adipokines, such as omentin and visfatin, are linked to obesity and its complications regulating inflammation and insulin resistance [6,7]. In addition, ghrelin, which is the main regulator of appetite, is secreted from the stomach during the fasting period and acts on the neurons of the hypothalamus [1,8].
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The correction of obesity-associated metabolic and inflammatory alteration is mandatory and can be achieved with weight reduction. Currently, bariatric therapies are more effective in inducing weight reduction and improving comorbidities then conservative approaches. Despite studies showing that bariatric therapies decrease body weight, improve insulin resistance and glucose metabolism, and may reduce inflammation, the exact mechanism is not well understood [1,9–12]. Several reports have described different plasma hormonal changes after bariatric surgery, but the data on the effect on the omentin and visfatin levels are sparse and conflicting [9–17]. Moreover, only a few studies have described hormonal changes, mainly ghrelin and leptin, after endoscopic placement of a balloon into the stomach (bioenterics intragastric balloon, BIB), which is a commonly used procedure, also as bridge therapy to surgery, due to its minimal invasiveness and good tolerability [18,19]. We recently found that in morbidly obese patients, weight reduction induced by BIB was connected with a decrease of leptin plasma levels and transient elevation of ghrelin levels, while the levels of these hormones remained relatively stable in obese patients treated with a low-calorie diet and physical effort [18]. There is no data on the effect of BIB therapy on plasma levels of omentin and visfatin. Knowledge about the timeline hormonal changes with weight loss will improve the understanding of the pathophysiological mechanism of obesity. The observed changes of adipokines and gastrointestinal hormones may determine the treatment efficacy of obesity and its complications and will improve patients’ selection to bariatric procedures. Therefore, the aim of the study was to assess: (i) the profile of ghrelin, leptin, adiponectin, visfatin, and omentin in obese patients; (ii) the timeline changes associated with weight reduction after endoscopic and surgical bariatric therapies; and (iii) their level changes in relation to the type of treatment and its efficacy. 2. Material and methods 2.1. Patients This was a prospective, observational study in which we recruited obese patients qualified to the endoscopic or surgical treatment of obesity in the Department of Gastroenterology and Internal Medicine, and the Department of General Surgery and Endocrinology, Medical University of Bialystok, Poland. The study protocol was approved by the local ethics committee and conducted with the guidelines of the 1975 Declaration of Helsinki. The inclusion criteria were: (i) BMI P 40 kg/m2 or BMI P 35 kg/m2 with at least one obesity concomitant disease (e.g. hypertension, diabetes mellitus, osteoarthritis, obstructive sleep apnea syndrome); (ii) a history of failed weight loss upon conservative treatment prior to the study; (iii) age P18 years; and (iv) written informed consent. The exclusion criteria were: (i) contraindications to surgical procedure or anesthesia; (ii) severe cardiac or chronic renal disease; (iii) malignancies; (iv) active or chronic infections; (v) coagulopathy; (vi) secondary causes of obesity (e.g.: genetic syndromes, thyroid disorders, polycystic ovary syndrome, Cushing disease, hypogonadism); (vii) gastrointestinal tract diseases (e.g.: previous surgical procedures, gallstones, chronic pancreatitis, ulcer disease); (viii) hernia hiatus oesophagi >3 cm; (ix) esophagitis grade C and D according to the endoscopic Los Angeles classification; (x) untreated depression or other neuropsychiatric disorders (e.g. bulimia nervosa, schizophrenia, personality disorders); (xi) alcohol intake 6 months before the inclusion and/or during the study period; (xii) drug addiction; (xiii) use of the following drugs: antipsychotic, antidepressants, and anticonvulsants; and (xiv) lack of collaboration with the patient.
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The control group consisted of sex- and age-matched healthy non-obese (BMI 18.5–24.9 kg/m2) volunteers. 2.2. Study protocol Ambulatory-recruited obese patients (n = 80) were then hospitalized in the Department of Gastroenterology and Internal Medicine, Medical University of Bialystok. After baseline evaluation (clinical and physical examination, laboratory tests, and upper gastrointestinal endoscopy) all patients were assessed by a team of specialists (internist, gastroenterologist, bariatric surgeon, anesthesiologist, dietician and endocrinologist if necessary). Next, all patients underwent endoscopic or surgical treatment (the type of performed procedure was in accordance with patients preferences) and were followed up at least one year. The following control visits were performed: at 8–12 weeks, 24–28 weeks, and 50–54 weeks (Supplementary Fig. 1). The control visits included clinical, physical, and anthropometric examination, blood tests and (if necessary) consultations with a dietician and psychologist. The following anthropometric measurements were collected: weight in kg and BMI (kg/m2). For the expression of weight loss after treatment the percentage of initial body weight (%IBW) and the percentage of total weight loss (%TWL) were used. Additionally, the percentage of excess weight loss (%EWL) after 50–54 weeks was calculated to assess adequate weight loss. The threshold of a minimum 50% EWL for surgically treated patients and a threshold of 25% EWL for endoscopic therapy were used a mark between success and failure of weight loss [20–24]. 2.3. Obesity treatment The endoscopic treatment of obesity (bioenterics intragastric balloon, BIB, Orbera, Allergan, Irvine, CA) was performed in the Department of Gastroenterology and Internal Medicine, Medical University of Bialystok. The BIB was endoscopically placed in the stomach under conscious sedation and filled with a volume of 500–550 saline with methylene blue. The device was successfully removed in all patients after 6 months. The surgical treatment of obesity was successfully performed in the Department of General Surgery and Endocrinology, Medical University of Bialystok, and consisted of either laparoscopic adjustable gastric banding (LAGB) or laparoscopic sleeve gastrectomy (LSG). 2.4. Biochemical parameters Blood samples from the peripheral vein for the measurement of hormones were collected from patients before and after treatment during consecutive control visits. After centrifugation, plasma and serum were stored at 80 °C before analysis. The peripheral blood samples from volunteers were used as controls. The measurements of leptin (Human Leptin Elisa, Biovendor), ghrelin (Human Ghrelin Total, RIA, Millipore), omentin-1 (Human Omentin-1 Elisa, Biovendor), visfatin (Visfatin, Elisa, Uscn Life Science Inc.), and adiponectin (Human Adiponectin, RIA, Millipore) were performed according to the manufacturer’s instructions. 2.5. Statistical analysis The STATISTICA 10.0 package was used for all analyses. Patients’ characteristics were described using the relative (%) frequency. Results were described as mean and SD for the quantitative variables with parametric distribution and as median and IQR for variables with non-parametric distribution. Comparisons of quantitative variables between patients and controls were performed using the Student’s t test or the Mann–Whitney U-test. For comparison of dependent variables between the consecutive
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visits within the groups, the Wilcoxon matched-pairs signed-ranks test or the paired sample t-test were used. The timeline changes of the body weight and the factor’s concentration in blood during all visits before and after treatment were analyzed by Friedman ANOVA. Comparison of variables between different types of treatment was done using ANOVA rank Kruskal–Wallis. Correlations were presented by means of Spearman’s coefficient. A p value less than 0.05 was considered as significant.
14.30–26.67) compared to the LABG group (median: 15.26, IQR: 13.90–17.39) and the BIB group (median: 12.14, IQR: 8.45–23.80) (p = 0.0150). Similarly, the %TWL after 50–54 weeks was the highest in the LSG group (median: 28.57, IQR: 22.86–33.33) compared to the LABG group (median: 16.82–15.62–26.90) and the BIB group (median: 15.50, IQR: 7.27–26.90) (p < 0.0001). The percentage of EWL (%EWL) was also the highest in the LSG group (median: 56.87, IQR: 40.30–70.10) compared to the LAGB group (median: 45.88, IQR: 32.80–53.10) and the BIB group (median: 27.20, IQR: 12.80–43.30) (p = 0.0022).
3. Results 3.2. Hormonal parameters in non-obese controls and obese patients before treatment
3.1. Subjects The inclusion and exclusion criteria met 67 obese patients (42 females/25 males; median age: 40 years, IQR: 34–52 years). Twenty-five patients were treated with the BIB. Surgical treatment was performed in 42 patients (LABG: n = 10; LSG: n = 32). No major complications related to the procedures were observed during perioperative period and follow-up. Twelve patients missed control visit 1. After 12 months, a total of 7 patients were lost from follow-up (7/67; 10.4%). Therefore, blood samples from visit 1 were available in 55 patients (55/67, 82.1%) and from visit 3 in 60 patients (60/67, 89.6%). Blood samples from 72 non-obese volunteers (48 females/24 males) with a median age of 42 years (IQR: 32–52 years) served as a control group. The median baseline body weight in kg, BMI, %IBW, and %TWL before and after treatment are presented in Table 1. A considerable weight loss was observed 24–28 and 50–54 weeks after procedures. Analyzing the anthropometric parameters in relation to the type of treatment, we found a statistically significant difference in weight loss at 24–28 and at 50–54 weeks after procedure. The sleeve gastrectomy patients lost more body weight compared to the other groups. The percentage of total weight loss (%TWL) after 24–28 weeks was the highest in the LSG group (median: 21.87, IQR: Table 1 Body weight before and after obesity treatment. Parameter
Median, IQR
P
Body weight (kg) Baseline 24–28 weeks after treatment 50–54 weeks after treatment
135.00 (120.00–146.00) 106.50 (99.00–121.00) 100.00 (90.00–119.00)
<0.0001
BMI (kg/m2) Baseline 24–28 weeks after treatment 50–54 weeks after treatment
45.40 (42.60–50.40) 36.60 (34.55–42.05) 34.85 (31.00–41.50)
<0.0001
%IBW 24–28 weeks after treatment 50–54 weeks after treatment
82.93 (75.57–87.86) 75.86 (70.37–84.30)
<0.0001
%TWL 24–28 weeks after treatment 50–54 weeks after treatment
17.07 (12.14–24.43) 24.11 (15.70–29.63)
<0.0001
BMI – body mass index, %IBW – the percentage of initial body weight; %TWL – the percentage of total weight loss.
Compared to non-obese healthy volunteers, obese patients at baseline have significantly higher levels of leptin and significantly lower levels of ghrelin, adiponectin, omentin, and visfatin in peripheral blood (Table 2). There were no significant differences in the median concentration of all hormones at baseline between the LSG, the LAGB, and the BIB groups. 3.3. Hormonal parameters during follow-up The timeline changes in the median concentration of hormones before and during follow-up are presented in Table 3. In obese patients, the median concentration of leptin significantly decreased during the follow-up and at 50–54 weeks after treatment remained significantly higher compared to non-obese controls (p < 0.001). We observed a significant increase of the median adiponectin concentration during the consecutive control visits. The adiponectin levels in obese patients, 50–54 weeks after treatment, were comparable to the levels observed in the control group (p = 0.7566). There was a slight decrease in the median ghrelin concentration over time, but at 50–54 weeks the levels were significantly lower compared to the baseline levels. The timeline changes in median concentration of omentin were not statistically significant. The visfatin levels tended to slightly increase over time (Table 3). At the last control visit, the median concentration of visfatin was significantly higher then its baseline concentration. Next, we tested the changes of hormone concentrations during follow-up in relation to the type of treatment. In Fig. 1A–E we show the levels of hormones between the study groups and within each group. There were no significant differences in the median concentration of all hormones at baseline and at 50–54 weeks after the treatment between three procedures. However, we found the various timeline changes of their levels in each study group. We observed a gradually significant increase of adiponectin levels in the LSG and LAGB groups, but not in the BIB group. The median adiponectin concentration at 50–54 weeks was significantly higher compared to its baseline values in the LAGB and LSG groups (Fig. 1A). The leptin levels gradually decreased in the surgical groups. However, in the BIB group at 8–12 and 20–24 weeks, this significantly decreased compared to the baseline values (p = 0.0029 and p = 0.0004, respectively), and then at the 50–54 weeks increased compared to the 24–28 weeks (p = 0.2860). Finally, at 50–54 weeks the leptin levels in the BIB
Table 2 Hormonal parameters in obese patients at baseline and non-obese controls. Parameter (median, IQR)
Obese patients
Non-obese controls
P
Leptin (ng/mL) Ghrelin (pg/mL) Adiponectin (ng/mL) Omentin (ng/mL) Visfatin (pg/mL)
52.52 (36.02–68.54) 577.98 (482.10–715.73) 6443.25 (3536.00–9778.00) 427.41 (295.96–588.79) 6715.86 (4848.20–8475.54)
6.08 (3.58–14.91) 945.57 (696.60–1399.51) 10136.00 (5576.00–14994.00) 548.68 (443.61–729.48) 8919.92 (5124.33–12078.31)
<0.0001 <0.0001 0.0015 <0.0001 0.0267
E. Wroblewski et al. / Cytokine 77 (2016) 56–62 Table 3 Time-dependent changes of hormone concentrations. Parameter
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3.4. Correlation between hormone levels and the anthropometric parameters
Median, IQR
Leptin (ng/mL)
Before 8–12 weeks after 24–28 weeks after 50–54 weeks after*
52.52 (36.02–68.54) 27.58 (15.13–42.23) 19.48 (10.05–31.62) 17.50 (12.56–34.68) p < 0.0001
Ghrelin (pg/mL)
Before 8–12 weeks after 24–28 weeks after 50–54 weeks after**
577.99 (482.10–715.73) 548.92 (453.74–689.05) 512.97 (423.49–821.20) 453.30 (405.11–641.69) p = 0.0606
Adiponectin (ng/mL)
Before 8–12 weeks after 24–28 weeks after 50–54 weeks after***
7270.00 (4293.00–13807.50) 7568.50 (4962.50–10854.50) 10292.38 (6088.50–13731.75) 14991.43 (6759.625–17032.38) p = 0.0046
Omentin (ng/mL)
Before 8–12 weeks after 24–28 weeks after 50–54 weeks after
427.40 (295.96–588.79) 415.20 (301.21–510.22) 442.79 (317.76–533.60) 422.57 (305.93–556.26) p = 0.5257
Visfatin (pg/mL)
Before 8–12 weeks after 24–28 weeks after 50–54 weeks after****
6715.87 (4848.19–8475.54) 6280.94 (4204.17–8861.16) 7313.13 (4566.44–11137.09) 8727.78 (6403.71–10235.38) p = 0.3361
The p value at 50–54 weeks compared to baseline values: * p < 0.0001. ** p = 0.0229. *** p = 0.0016. **** p = 0.0397.
group were slightly, but not significantly lower than their baseline values (Fig. 1C). The visfatin levels decreased at 8–12 weeks in the BIB and LAGB groups, but not in the LSG groups, and at 24–28 and 50–54 weeks gradually increased in all groups (Fig. 1D). There were no significant changes in the omentin levels between groups (Fig. 1E).
Next we analyzed the correlations between the baseline hormone concentrations and the anthropometric parameters in all obese patients. We found that the baseline ghrelin levels correlated with BMI before treatment (Rs = 0.2941; p = 0.0157) and 24–28 weeks after treatment (Rs = 0.3065; p = 0.0138). Moreover, the baseline leptin levels correlated with BMI before (Supplementary Fig. 2) and 24–28 weeks, and 50–54 weeks after treatment. The adiponectin levels at baseline correlated with weight loss (%TWL) after 24–28 weeks (Rs = 0.2773; p = 0.025). Moreover, we found that at 24–28 weeks the leptin levels correlated with % TWL (Rs = 0.2942; p = 0.0361) and at 50–54 weeks it correlated with BMI (Rs = 0.3968; p = 0.0124) and %TWL (Rs = 0.6544; p < 0.001) (Fig. 2A). Then, we tested if there were correlations between the levels of hormones before and after the treatment. We found a few weak, but statistically significant correlations. At baseline, the adiponectin levels negatively correlated with the leptin levels (Rs = 0.3031; p = 0.0014) and positively with the ghrelin levels (Rs = 0.2356; p = 0.0087), and the visfatin levels (Rs = 0.3074; p = 0.0005). Additionally, the leptin levels correlated negatively with the levels of ghrelin (Rs = 0.4233; p < 0.0001) and omentin (Rs = 0.3191; p = 0.003). There was also a correlation between the levels of visfatin and omentin (Rs = 0.3703; p < 0.0001). After the treatment, the omentin levels correlated with the levels of adiponectin (Rs = 0.2705; p = 0.0080), ghrelin (Rs = 0.2121; p = 0.0268), visfatin (Rs = 0.2655; p = 0.0049), and leptin (Rs = 0.2055; p = 0.0032). Moreover, the ghrelin levels correlated negatively with the leptin levels (Rs = 0.3367; p = 0.0003). There was a correlation between the adiponectin and visfatin levels (Rs = 0.3414; p = 0.0006). 3.5. Hormone levels and the percentage of excess weight loss at 50– 54 weeks At 50–54 weeks after treatment, the %EWL less than 25% had 11 patients in the BIB group (11/25; 44.8%). The %EWL less than 50% in
Fig. 1. Median concentration of hormones in relation to the type of treatment. (A). Adiponectin, p value between the levels at baseline and 50–54 weeks: ⁄0.0173; ] 0.0186; § 0.2758. (B). Ghrelin, p value between the levels at baseline and 50–54 weeks: ⁄0.7532; ] 0.0051; § 0.3824. (C). Leptin, p value between the levels at baseline and 50–54 weeks: ⁄ 0.0796; ] <0.0001; § 0.2076. (D). Visfatin, p value between the levels at baseline and 50–54 weeks: ⁄0.1159; ] 0.0457; § 0.9721. (E). Omentin, p value between the levels at baseline and 50–54 weeks: ⁄0.0277; ] 0.9584; § 0.2213. BIB – bioenterics intragastric balloon, LAGB – laparoscopic adjustable gastric banding, SG – sleeve gastrectomy.
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Fig. 2. The leptin levels in relation to the weight loss at 50–54 weeks. (A). Correlation between the leptin concentration and the percentage of total weight loss, %TWL – percentage of total weight loss. (B). The median leptin concentration in relation to the recommended percentage of excess weight lost, %EWL – percentage of excess weight loss.
the surgical groups had 16 patients (16/42; 38.1%) (LABG group: 5 patients, LSG group: 11 patients). Analyzing the levels of hormones between the groups which achieved and did not achieve the recommended threshold of 25% EWL (BIB) or 50% EWL (LAGB, LSG), we found no significant differences in none except the leptin concentration. The patients who achieved recommended %EWL had significantly lower leptin levels at 50–54 weeks than those patients with a lower decrease of %EWL (median: 14.37, IQR: 9.16–28.23 vs 24.85, IQR: 17.29–48.46, p = 0.0182) (Fig. 2B). 4. Discussion Weight reduction induced by bariatric therapies is the most effective strategy for the correction of obesity-associated metabolic and inflammatory alterations. However, the exact mechanism is not well understood. We analyzed the blood profile of hormones in obese patients compared to non-obese patients and the effect of weight loss on their levels following endoscopic and surgical bariatric therapies. Our study showed that the impact of weight reduction on hormonal levels is very complex due to the complexity of hormonal interactions and timeline changes after therapy. We found that the weight loss itself, rather than the procedure type used to reduce body mass, is responsible for the observed hormonal changes, and that the effectiveness of bariatric therapy depend on the size of these changes. Obesity is proposed to be a chronic low-grade inflammatory condition associated with the alteration in the production of several growth factors and pro- and anti-inflammatory cytokines [1,2]. First, we confirmed that obese patients compared to nonobese controls have higher blood levels of leptin and lower levels of ghrelin and adiponectin. We found a negative correlation between the levels of adiponectin and leptin. The chronic subinflammatory state observed in obesity may result from the elevated levels of leptin and decreased levels of adiponectin, and can be responsible for complications, including different types of cancer, as these hormones have opposite effects on cell functions [2–6]. Adiponectin inhibits cell proliferation and the expression of tumor necrosis factor-a (TNF-a), interferon gamma, and interleukin-6 (Il6). It increases Il-10 and tissue inhibitor of metalloproteinases 1 activity by AMP-activated protein kinase (AMPK) signaling [2– 4,25]. Leptin upregulates TNF-a and Il-6, increases insulin resis-
tance, inhibits apoptosis and stimulates cell proliferation, migration and invasion of tumor cells. In turn, Il-6 and TNF-a increase leptin expression in adipose tissue and inhibit adiponectin expression [2–6]. There can be also a crosstalk between the levels of leptin and adiponectin. One study assessed the mechanism of protective effect of adiponectin on vascular extracellular matrix (ECM) remodeling and suggested that adiponectin disrupts the leptin-induced vascular ECM remodeling via adiponectin receptor 1 and enhanced AMPK signaling in endothelial cells, which in turn, promotes SOCS3 up-regulation in smooth muscle cells to inhibit phosphorylation of STAT3 simulated by leptin [26]. More importantly, we observed a significant decrease in the blood levels of leptin and an increase of the adiponectin levels at 50–54 weeks after treatment compared to their baseline values. Moreover, the changes in their levels correlated with %TWL. These observations can explain the positive effect of weight loss on complications by the regulation of adiponectin-leptin imbalance. Additionally, we analyzed the visfatin levels that can be a missing link between endocrine metabolic disorders and immunity. However, data are conflicting [6,9,14,15,25]. Visfatin is produced by visceral adipose tissue and is known as a pre-B cell colonyenhancing factor that mediates inflammatory response by induction of Il-6 and TNF-a, but its higher concentration augments the expression of anti-inflammatory cytokines such as Il-10 [6,9,27]. In comparison to non-obese patients, we observed lower visfatin levels in obese patients which were significantly higher at 50– 54 weeks after treatment compared to their baseline levels. However, its levels did not correlate with weight loss. This supports other authors’ observations that visfatin levels tend to be increased with weight loss [9,14]. We found a positive correlation of its levels with the adiponectin and omentin levels before and after therapy. Visfatin seems to have more complex functions and the explanation for its increase after weight loss is unclear. It may play a role in improving insulin sensitivity after weight loss as it is an insulinmimetic factor [9]. We confirmed that obese patients had decreased omentin levels compared to non-obese patients and that its levels correlated negatively with the leptin levels [7,17]. In contrast to other studies [18,28], weight reduction did not significantly affect its blood levels. The beneficial effects of omentin can be explained by the observation that treatment with omentin led to the relaxation of endothelial cells, increased phosphorylation of
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nitric oxide synthase and AMPK, reduction of cyclooxygenase-2 expression and TNF-a-induced activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-jb) [29]. As it was described above, we found several correlations between levels of tested hormones, before and after treatment. The interactions between all circulating and local factors contribute to obesity and its complications, and dictate the effectiveness of weight loss therapies. In our study, in patients who achieved the recommended %EWL the final leptin concentration was lower than in patients with lower %EWL. The baseline body weight between the both groups of patients was similar. The measurement of the leptin concentration may be helpful to determine which patients will have the greatest benefits from bariatric therapies. The question arises from this observation – whatever patients with insufficient weight loss have increased risk of complications due to higher leptin levels. Different types of bariatric therapies are used for reducing weight with various efficacy [9–12,18,24,30–33]. As we expected, the highest weight loss was observed after LSG and the lowest after BIB therapy. Although the BIB therapy was effective in reducing the body weight within the first 6 months in all patients, its efficacy decreased within the months following the balloon’s removal – only in this group a slight weight gain from its nadir value was observed in 48% of patients, and 8 patients (32%) were referred for bariatric surgery (unpublished results). More importantly, recent data support that weight loss itself and not the manner by which weight loss is achieved is the most important for the correction of obesity-related complications [32]. We also did not report statistically significant differences in the median baseline and final concentrations of hormones between therapies. However, we observed some variations in their levels during the follow-up. The adiponectin levels in the surgical groups increased at all study time points, especially in the LAGB group, but in the BIB group there was a slight decrease at 8–12 weeks followed by an increase at 24– 28 weeks and then a decrease at 50–54 weeks. The leptin levels decreased in all groups at 24–28 weeks and were still decreasing at 50–54 weeks in the surgical groups but not in the BIB group in which we observed the levels increase. Six months after BIB removal, adiponectin and leptin levels tended to gradually return toward baseline. In summary, the timeline changes in hormones levels were the most stable in the groups treated with bariatric surgery, especially in the LSG group. Therefore, the LSG providing the highest weight loss with the smallest hormonal variation over time may be a superior procedure as a first stage of obesity treatment. Our study has some limitations. First, this was a nonrandomized, but prospective and observational study. The number of patients that underwent each bariatric procedure was different. However, the main aim of this study was to analyze the effect of weight loss on the blood levels of hormones, their timeline changes and to assess their correlation with body weight and the amount of weight loss. Further studies with randomization to different procedures would be helpful to better understand the mechanism of weight reduction, although it would be very difficult to perform it. The cooperation with obese patients and monitoring of diet and physical effort during the follow-up is not always reliable. Although it was not the aim of this report to assess the obesityrelated complications and the study duration was too short, we believe that the observed hormonal changes may elucidate well known beneficial long-term effects of weight loss. In conclusion, our study supports previous observations that weight loss itself, rather than the procedure type used to reduce body mass, is responsible for hormonal ameliorations in obese patients. Moreover, the results of this study provide more explanations about the effect of weight loss and bariatric therapies on the hormonal changes in blood and explain, at least in part, why some patients have insufficient weight loss after treatment.
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Sources of funding Polish National Science Center Grant No. N N402 456839. Appendix A. Supplementary material Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.cyto.2015.10.013. References [1] A. Acosta, B.K. Abu Dayyeh, J.D. Port, M. Camilleri, Recent advanced in clinical practice challenges and opportunities in the management of obesity, Gut 63 (2014) 687–695. [2] H. Tilg, A.R. Moschen, Mechanism behind the link between obesity and gastrointestinal cancers, Best Pract. Res. Clin. Gastroenterol. 28 (2014) 599– 610. [3] N. Ouchi, J.L. Parker, J.J. Lugus, K. Walsh, Adipokines in inflammation and metabolic disease, Nat. Rev. Immunol. 11 (2011) 85–97. [4] E. Nigro, O. Scudiero, M.L. Monaco, A. Palmieri, G. Mazzarella, C. Costagliola, A. Bianco, A. Daniele, New insight into adiponectin role in obesity and obesityrelated diseases, Biomed. Res. Int. 2014 (2014) 658913. [5] H. Münzberg, C.D. Morrison, Structure, production and signaling of leptin, Metabolism 64 (2015) 13–23. [6] E.A. Al-Suhaimi, A. Shehzad, Leptin, resistin and visfatin: the missing link between endocrine metabolic disorders and immunity, Eur. J. Med. Res. 18 (2013) 12. [7] T. Auguet, Y. Quintero, D. Riesco, B. Morancho, X. Terra, A. Crescenti, M. Broch, C. Aguilar, M. Olona, J.A. Porras, M. Hernandez, F. Sabench, D. del Castillo, C. Richart, New adipokines vaspin and omentin. Circulating levels and gene expression in adipose tissue from morbidly obese women, BMC Med. Genet. 12 (2011) 60. [8] P.J. Verhulst, I. Depoortere, Ghrelin’s second life: from appetite stimulator to glucose regulator, World J. Gastroenterol. 18 (2012) 3183–3195. [9] Z. Goktas, N. Moustaid-Moussa, C.L. Shen, M. Boylan, H. Mo, S. Wang, Effects of bariatric surgery on adipokine-induced inflammation and insulin resistance, Front. Endocrinol. (Lausanne) 10 (4) (2013) 69. [10] E. Arismendi, E. Rivas, A. Agustí, J. Ríos, E. Barreiro, J. Vidal, R. Rodriguez-Roisin, The systemic inflammome of severe obesity before and after bariatric surgery, PLoS ONE 9 (2014) e107859. [11] V. Gumbau, M. Bruna, E. Canelles, M. Guaita, C. Mulas, C. Basés, I. Celma, J. Puche, G. Marcaida, M. Oviedo, A. Vázquez, A prospective study on inflammatory parameters in obese patients after sleeve gastrectomy, Obes. Surg. 24 (2014) 903–908. [12] H.R. Hady, J. Dadan, M. Luba, The influence of laparoscopic sleeve gastrectomy on metabolic syndrome parameters in obese patients in own material, Obes. Surg. 22 (2012) 13–22. [13] H.R. Hady, J. Dadan, P. Gołaszewski, 100 obese patients after laparoscopic adjustable gastric banding – the influence on BMI, ghrelin and insulin concentration, parameters of lipid balance and co-morbidities, Adv. Med. Sci. 57 (2012) 58–64. [14] J.I. Botella-Carretero, M. Luque-Ramírez, F. Alvarez-Blasco, R. Peromingo, J.L. San Millán, H.F. Escobar-Morreale, The increase in serum visfatin after bariatric surgery in morbidly obese women is modulated by weight loss, waist circumference, and presence or absence of diabetes before surgery, Obes. Surg. 18 (2008) 1000–1006. [15] M.J. Hosseinzadeh-Attar, A. Golpaie, L. Janani, H. Derakhshanian, Effect of weight reduction following bariatric surgery on serum visfatin and adiponectin levels in morbidly obese subjects, Obes. Facts 6 (2013) 193–202. [16] A. Siejka, J. Jankiewicz-Wika, K. Kołomecki, J. Cywin´ski, K. Piestrzeniewicz, J. Swie˛tosławski, H. Ste˛pien´, J. Komorowski, Long-term impact of vertical banded gastroplasty (VBG) on plasma concentration of leptin, soluble leptin receptor, ghrelin, omentin-1, obestatin, and retinol binding protein 4 (RBP4) in patients with severe obesity, Cytokine 64 (2013) 490–493. [17] M. Urbanová, I. Dostálová, P. Trachta, J. Drápalová, P. Kaválková, D. Haluzíková, M. Matoulek, Z. Lacinová, M. Mráz, M. Kasalicky´, M. Haluzík, Serum concentrations and subcutaneous adipose tissue mRNA expression of omentin in morbid obesity and type 2 diabetes mellitus: the effect of verylow-calorie diet, physical activity and laparoscopic sleeve gastrectomy, Physiol. Res. 63 (2014) 207–218. [18] M. Konopko-Zubrzycka, A. Baniukiewicz, E. Wróblewski, I. Kowalska, W. Zarzycki, M. Górska, A. Dabrowski, The effect of intragastric balloon on plasma ghrelin, leptin, and adiponectin levels in patients with morbid obesity, J. Clin. Endocrinol. Metab. 94 (2009) 1644–1649. [19] M. Nikolic, M. Boban, N. Ljubicic, V. Supanc, G. Mirosevic, B. Pezo Nikolic, R. Krpan, L. Posavec, V. Zjacic-Rotkvic, M. Bekavac-Beslin, P. Gacina, Morbidly obese are ghrelin and leptin hyporesponders with lesser intragastric balloon treatment efficiency: ghrelin and leptin changes in relation to obesity treatment, Obes. Surg. 21 (2011) 1597–1604. [20] J.P. Szczepaniak, M.L. Owens, H. Shukla, J. Perglos, W. Garner, Comparability of weight loss reporting after gastric bypass and sleeve gastrectomy using BOLD Data 2008–2011, Obes. Surg. 25 (2015) 788–795.
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Cytokine journal homepage: www.journals.elsevier.com/cytokine
Variation in blood levels of hormones in obese patients following weight reduction induced by endoscopic and surgical bariatric therapies Eugeniusz Wroblewski a, Agnieszka Swidnicka-Siergiejko a,⇑, Hady Razak Hady b, Magdalena Luba b, Marzena Konopko a, Krzysztof Kurek a, Jacek Dadan b, Andrzej Dabrowski a a b
Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, Poland 1st Clinical Department of General and Endocrine Surgery, Medical University of Bialystok, Poland
a r t i c l e
i n f o
Article history: Received 31 May 2015 Received in revised form 2 October 2015 Accepted 26 October 2015 Available online 2 November 2015 Keywords: Obesity Adipokines Weight loss Gastric balloon Bariatric surgery
a b s t r a c t Background: Beneficial clinical effects of weight reduction following bariatric therapies is not fully understood and maybe related to the complex interactions between leptin, adiponectin, visfatin, omentin, and ghrelin. The aim of study was to investigate their timeline changes associated with weight reduction and their profile in relation to the type of treatment and its efficacy. Methods: Circulating hormones levels were analyzed before and after endoscopic and surgical procedures in 67 obese patients and compared to non-obese healthy controls. Results: Obese patients had higher leptin levels and lower levels of adiponectin, visfatin, omentin, and ghrelin than non-obese controls. During the consecutive follow-up visits after treatment, there was a gradual decrease in leptin levels and an increase in adiponectin levels to the levels observed in nonobese. At 50–54 weeks, the ghrelin levels were lower and the levels of adiponectin and visfatin, but not omentin, were higher compared to their baseline values. BMI correlated with ghrelin and leptin levels. The percentage of total weight loss correlated positively with adiponectin levels and negatively with leptin levels. Patients with adequate weight loss had a significantly lower leptin concentration than those with treatment failure. There were timeline variations in hormone levels between endoscopic and bariatric therapies, however there were no significant differences in the median their concentration at 50–54 weeks after therapy. Conclusion: Our study supports observations that weight loss itself, rather than the procedure type, is responsible for hormonal variation. The leptin levels reflect the best the body weight changes after bariatric therapies. Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction Obesity is among the fastest growing diseases worldwide that increases the risk of the numbers of complications including cardiovascular diseases, diabetes mellitus and cancers. The mechanism how obesity contributes to complications is more complex and includes gastrointestinal hormones, adipokines, insulin and
Abbreviations: BIB, bioenterics intragastric balloon; LAGBl, aparoscopic adjustable gastric banding; LSG, laparoscopic sleeve gastrectomy; %IBW, the percentage of initial body weight; %EWL, the percentage of excess weight loss; %TWL, the percentage of total weight loss. ⇑ Corresponding author at: Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, Ul. M. Sklodowskiej-Curie 24a, 15-276 Bialystok, Poland. E-mail address: [email protected] (A. Swidnicka-Siergiejko). http://dx.doi.org/10.1016/j.cyto.2015.10.013 1043-4666/Ó 2015 Elsevier Ltd. All rights reserved.
insulin-like growth factor signaling pathways, inflammation, immune responses, gut-brain axis, hypothalamic nervous system, and gut microbiota. Dysregulation in these systems associated with fat accumulation may lead to chronic inflammation and then to cancer development [1,2]. Among adipokines expressed by white adipose tissue, adiponectin has a protective role as it regulates insulin sensitivity, has anti-inflammatory, and antiatherogenic properties [3,4]. Leptin regulates energy hemostasis by controlling satiety and body weight, plays a role in angiogenesis and it is a key proinflammatory factor modulating the immune system [5,6]. Recent data suggests that novel adipokines, such as omentin and visfatin, are linked to obesity and its complications regulating inflammation and insulin resistance [6,7]. In addition, ghrelin, which is the main regulator of appetite, is secreted from the stomach during the fasting period and acts on the neurons of the hypothalamus [1,8].
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The correction of obesity-associated metabolic and inflammatory alteration is mandatory and can be achieved with weight reduction. Currently, bariatric therapies are more effective in inducing weight reduction and improving comorbidities then conservative approaches. Despite studies showing that bariatric therapies decrease body weight, improve insulin resistance and glucose metabolism, and may reduce inflammation, the exact mechanism is not well understood [1,9–12]. Several reports have described different plasma hormonal changes after bariatric surgery, but the data on the effect on the omentin and visfatin levels are sparse and conflicting [9–17]. Moreover, only a few studies have described hormonal changes, mainly ghrelin and leptin, after endoscopic placement of a balloon into the stomach (bioenterics intragastric balloon, BIB), which is a commonly used procedure, also as bridge therapy to surgery, due to its minimal invasiveness and good tolerability [18,19]. We recently found that in morbidly obese patients, weight reduction induced by BIB was connected with a decrease of leptin plasma levels and transient elevation of ghrelin levels, while the levels of these hormones remained relatively stable in obese patients treated with a low-calorie diet and physical effort [18]. There is no data on the effect of BIB therapy on plasma levels of omentin and visfatin. Knowledge about the timeline hormonal changes with weight loss will improve the understanding of the pathophysiological mechanism of obesity. The observed changes of adipokines and gastrointestinal hormones may determine the treatment efficacy of obesity and its complications and will improve patients’ selection to bariatric procedures. Therefore, the aim of the study was to assess: (i) the profile of ghrelin, leptin, adiponectin, visfatin, and omentin in obese patients; (ii) the timeline changes associated with weight reduction after endoscopic and surgical bariatric therapies; and (iii) their level changes in relation to the type of treatment and its efficacy. 2. Material and methods 2.1. Patients This was a prospective, observational study in which we recruited obese patients qualified to the endoscopic or surgical treatment of obesity in the Department of Gastroenterology and Internal Medicine, and the Department of General Surgery and Endocrinology, Medical University of Bialystok, Poland. The study protocol was approved by the local ethics committee and conducted with the guidelines of the 1975 Declaration of Helsinki. The inclusion criteria were: (i) BMI P 40 kg/m2 or BMI P 35 kg/m2 with at least one obesity concomitant disease (e.g. hypertension, diabetes mellitus, osteoarthritis, obstructive sleep apnea syndrome); (ii) a history of failed weight loss upon conservative treatment prior to the study; (iii) age P18 years; and (iv) written informed consent. The exclusion criteria were: (i) contraindications to surgical procedure or anesthesia; (ii) severe cardiac or chronic renal disease; (iii) malignancies; (iv) active or chronic infections; (v) coagulopathy; (vi) secondary causes of obesity (e.g.: genetic syndromes, thyroid disorders, polycystic ovary syndrome, Cushing disease, hypogonadism); (vii) gastrointestinal tract diseases (e.g.: previous surgical procedures, gallstones, chronic pancreatitis, ulcer disease); (viii) hernia hiatus oesophagi >3 cm; (ix) esophagitis grade C and D according to the endoscopic Los Angeles classification; (x) untreated depression or other neuropsychiatric disorders (e.g. bulimia nervosa, schizophrenia, personality disorders); (xi) alcohol intake 6 months before the inclusion and/or during the study period; (xii) drug addiction; (xiii) use of the following drugs: antipsychotic, antidepressants, and anticonvulsants; and (xiv) lack of collaboration with the patient.
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The control group consisted of sex- and age-matched healthy non-obese (BMI 18.5–24.9 kg/m2) volunteers. 2.2. Study protocol Ambulatory-recruited obese patients (n = 80) were then hospitalized in the Department of Gastroenterology and Internal Medicine, Medical University of Bialystok. After baseline evaluation (clinical and physical examination, laboratory tests, and upper gastrointestinal endoscopy) all patients were assessed by a team of specialists (internist, gastroenterologist, bariatric surgeon, anesthesiologist, dietician and endocrinologist if necessary). Next, all patients underwent endoscopic or surgical treatment (the type of performed procedure was in accordance with patients preferences) and were followed up at least one year. The following control visits were performed: at 8–12 weeks, 24–28 weeks, and 50–54 weeks (Supplementary Fig. 1). The control visits included clinical, physical, and anthropometric examination, blood tests and (if necessary) consultations with a dietician and psychologist. The following anthropometric measurements were collected: weight in kg and BMI (kg/m2). For the expression of weight loss after treatment the percentage of initial body weight (%IBW) and the percentage of total weight loss (%TWL) were used. Additionally, the percentage of excess weight loss (%EWL) after 50–54 weeks was calculated to assess adequate weight loss. The threshold of a minimum 50% EWL for surgically treated patients and a threshold of 25% EWL for endoscopic therapy were used a mark between success and failure of weight loss [20–24]. 2.3. Obesity treatment The endoscopic treatment of obesity (bioenterics intragastric balloon, BIB, Orbera, Allergan, Irvine, CA) was performed in the Department of Gastroenterology and Internal Medicine, Medical University of Bialystok. The BIB was endoscopically placed in the stomach under conscious sedation and filled with a volume of 500–550 saline with methylene blue. The device was successfully removed in all patients after 6 months. The surgical treatment of obesity was successfully performed in the Department of General Surgery and Endocrinology, Medical University of Bialystok, and consisted of either laparoscopic adjustable gastric banding (LAGB) or laparoscopic sleeve gastrectomy (LSG). 2.4. Biochemical parameters Blood samples from the peripheral vein for the measurement of hormones were collected from patients before and after treatment during consecutive control visits. After centrifugation, plasma and serum were stored at 80 °C before analysis. The peripheral blood samples from volunteers were used as controls. The measurements of leptin (Human Leptin Elisa, Biovendor), ghrelin (Human Ghrelin Total, RIA, Millipore), omentin-1 (Human Omentin-1 Elisa, Biovendor), visfatin (Visfatin, Elisa, Uscn Life Science Inc.), and adiponectin (Human Adiponectin, RIA, Millipore) were performed according to the manufacturer’s instructions. 2.5. Statistical analysis The STATISTICA 10.0 package was used for all analyses. Patients’ characteristics were described using the relative (%) frequency. Results were described as mean and SD for the quantitative variables with parametric distribution and as median and IQR for variables with non-parametric distribution. Comparisons of quantitative variables between patients and controls were performed using the Student’s t test or the Mann–Whitney U-test. For comparison of dependent variables between the consecutive
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visits within the groups, the Wilcoxon matched-pairs signed-ranks test or the paired sample t-test were used. The timeline changes of the body weight and the factor’s concentration in blood during all visits before and after treatment were analyzed by Friedman ANOVA. Comparison of variables between different types of treatment was done using ANOVA rank Kruskal–Wallis. Correlations were presented by means of Spearman’s coefficient. A p value less than 0.05 was considered as significant.
14.30–26.67) compared to the LABG group (median: 15.26, IQR: 13.90–17.39) and the BIB group (median: 12.14, IQR: 8.45–23.80) (p = 0.0150). Similarly, the %TWL after 50–54 weeks was the highest in the LSG group (median: 28.57, IQR: 22.86–33.33) compared to the LABG group (median: 16.82–15.62–26.90) and the BIB group (median: 15.50, IQR: 7.27–26.90) (p < 0.0001). The percentage of EWL (%EWL) was also the highest in the LSG group (median: 56.87, IQR: 40.30–70.10) compared to the LAGB group (median: 45.88, IQR: 32.80–53.10) and the BIB group (median: 27.20, IQR: 12.80–43.30) (p = 0.0022).
3. Results 3.2. Hormonal parameters in non-obese controls and obese patients before treatment
3.1. Subjects The inclusion and exclusion criteria met 67 obese patients (42 females/25 males; median age: 40 years, IQR: 34–52 years). Twenty-five patients were treated with the BIB. Surgical treatment was performed in 42 patients (LABG: n = 10; LSG: n = 32). No major complications related to the procedures were observed during perioperative period and follow-up. Twelve patients missed control visit 1. After 12 months, a total of 7 patients were lost from follow-up (7/67; 10.4%). Therefore, blood samples from visit 1 were available in 55 patients (55/67, 82.1%) and from visit 3 in 60 patients (60/67, 89.6%). Blood samples from 72 non-obese volunteers (48 females/24 males) with a median age of 42 years (IQR: 32–52 years) served as a control group. The median baseline body weight in kg, BMI, %IBW, and %TWL before and after treatment are presented in Table 1. A considerable weight loss was observed 24–28 and 50–54 weeks after procedures. Analyzing the anthropometric parameters in relation to the type of treatment, we found a statistically significant difference in weight loss at 24–28 and at 50–54 weeks after procedure. The sleeve gastrectomy patients lost more body weight compared to the other groups. The percentage of total weight loss (%TWL) after 24–28 weeks was the highest in the LSG group (median: 21.87, IQR: Table 1 Body weight before and after obesity treatment. Parameter
Median, IQR
P
Body weight (kg) Baseline 24–28 weeks after treatment 50–54 weeks after treatment
135.00 (120.00–146.00) 106.50 (99.00–121.00) 100.00 (90.00–119.00)
<0.0001
BMI (kg/m2) Baseline 24–28 weeks after treatment 50–54 weeks after treatment
45.40 (42.60–50.40) 36.60 (34.55–42.05) 34.85 (31.00–41.50)
<0.0001
%IBW 24–28 weeks after treatment 50–54 weeks after treatment
82.93 (75.57–87.86) 75.86 (70.37–84.30)
<0.0001
%TWL 24–28 weeks after treatment 50–54 weeks after treatment
17.07 (12.14–24.43) 24.11 (15.70–29.63)
<0.0001
BMI – body mass index, %IBW – the percentage of initial body weight; %TWL – the percentage of total weight loss.
Compared to non-obese healthy volunteers, obese patients at baseline have significantly higher levels of leptin and significantly lower levels of ghrelin, adiponectin, omentin, and visfatin in peripheral blood (Table 2). There were no significant differences in the median concentration of all hormones at baseline between the LSG, the LAGB, and the BIB groups. 3.3. Hormonal parameters during follow-up The timeline changes in the median concentration of hormones before and during follow-up are presented in Table 3. In obese patients, the median concentration of leptin significantly decreased during the follow-up and at 50–54 weeks after treatment remained significantly higher compared to non-obese controls (p < 0.001). We observed a significant increase of the median adiponectin concentration during the consecutive control visits. The adiponectin levels in obese patients, 50–54 weeks after treatment, were comparable to the levels observed in the control group (p = 0.7566). There was a slight decrease in the median ghrelin concentration over time, but at 50–54 weeks the levels were significantly lower compared to the baseline levels. The timeline changes in median concentration of omentin were not statistically significant. The visfatin levels tended to slightly increase over time (Table 3). At the last control visit, the median concentration of visfatin was significantly higher then its baseline concentration. Next, we tested the changes of hormone concentrations during follow-up in relation to the type of treatment. In Fig. 1A–E we show the levels of hormones between the study groups and within each group. There were no significant differences in the median concentration of all hormones at baseline and at 50–54 weeks after the treatment between three procedures. However, we found the various timeline changes of their levels in each study group. We observed a gradually significant increase of adiponectin levels in the LSG and LAGB groups, but not in the BIB group. The median adiponectin concentration at 50–54 weeks was significantly higher compared to its baseline values in the LAGB and LSG groups (Fig. 1A). The leptin levels gradually decreased in the surgical groups. However, in the BIB group at 8–12 and 20–24 weeks, this significantly decreased compared to the baseline values (p = 0.0029 and p = 0.0004, respectively), and then at the 50–54 weeks increased compared to the 24–28 weeks (p = 0.2860). Finally, at 50–54 weeks the leptin levels in the BIB
Table 2 Hormonal parameters in obese patients at baseline and non-obese controls. Parameter (median, IQR)
Obese patients
Non-obese controls
P
Leptin (ng/mL) Ghrelin (pg/mL) Adiponectin (ng/mL) Omentin (ng/mL) Visfatin (pg/mL)
52.52 (36.02–68.54) 577.98 (482.10–715.73) 6443.25 (3536.00–9778.00) 427.41 (295.96–588.79) 6715.86 (4848.20–8475.54)
6.08 (3.58–14.91) 945.57 (696.60–1399.51) 10136.00 (5576.00–14994.00) 548.68 (443.61–729.48) 8919.92 (5124.33–12078.31)
<0.0001 <0.0001 0.0015 <0.0001 0.0267
E. Wroblewski et al. / Cytokine 77 (2016) 56–62 Table 3 Time-dependent changes of hormone concentrations. Parameter
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3.4. Correlation between hormone levels and the anthropometric parameters
Median, IQR
Leptin (ng/mL)
Before 8–12 weeks after 24–28 weeks after 50–54 weeks after*
52.52 (36.02–68.54) 27.58 (15.13–42.23) 19.48 (10.05–31.62) 17.50 (12.56–34.68) p < 0.0001
Ghrelin (pg/mL)
Before 8–12 weeks after 24–28 weeks after 50–54 weeks after**
577.99 (482.10–715.73) 548.92 (453.74–689.05) 512.97 (423.49–821.20) 453.30 (405.11–641.69) p = 0.0606
Adiponectin (ng/mL)
Before 8–12 weeks after 24–28 weeks after 50–54 weeks after***
7270.00 (4293.00–13807.50) 7568.50 (4962.50–10854.50) 10292.38 (6088.50–13731.75) 14991.43 (6759.625–17032.38) p = 0.0046
Omentin (ng/mL)
Before 8–12 weeks after 24–28 weeks after 50–54 weeks after
427.40 (295.96–588.79) 415.20 (301.21–510.22) 442.79 (317.76–533.60) 422.57 (305.93–556.26) p = 0.5257
Visfatin (pg/mL)
Before 8–12 weeks after 24–28 weeks after 50–54 weeks after****
6715.87 (4848.19–8475.54) 6280.94 (4204.17–8861.16) 7313.13 (4566.44–11137.09) 8727.78 (6403.71–10235.38) p = 0.3361
The p value at 50–54 weeks compared to baseline values: * p < 0.0001. ** p = 0.0229. *** p = 0.0016. **** p = 0.0397.
group were slightly, but not significantly lower than their baseline values (Fig. 1C). The visfatin levels decreased at 8–12 weeks in the BIB and LAGB groups, but not in the LSG groups, and at 24–28 and 50–54 weeks gradually increased in all groups (Fig. 1D). There were no significant changes in the omentin levels between groups (Fig. 1E).
Next we analyzed the correlations between the baseline hormone concentrations and the anthropometric parameters in all obese patients. We found that the baseline ghrelin levels correlated with BMI before treatment (Rs = 0.2941; p = 0.0157) and 24–28 weeks after treatment (Rs = 0.3065; p = 0.0138). Moreover, the baseline leptin levels correlated with BMI before (Supplementary Fig. 2) and 24–28 weeks, and 50–54 weeks after treatment. The adiponectin levels at baseline correlated with weight loss (%TWL) after 24–28 weeks (Rs = 0.2773; p = 0.025). Moreover, we found that at 24–28 weeks the leptin levels correlated with % TWL (Rs = 0.2942; p = 0.0361) and at 50–54 weeks it correlated with BMI (Rs = 0.3968; p = 0.0124) and %TWL (Rs = 0.6544; p < 0.001) (Fig. 2A). Then, we tested if there were correlations between the levels of hormones before and after the treatment. We found a few weak, but statistically significant correlations. At baseline, the adiponectin levels negatively correlated with the leptin levels (Rs = 0.3031; p = 0.0014) and positively with the ghrelin levels (Rs = 0.2356; p = 0.0087), and the visfatin levels (Rs = 0.3074; p = 0.0005). Additionally, the leptin levels correlated negatively with the levels of ghrelin (Rs = 0.4233; p < 0.0001) and omentin (Rs = 0.3191; p = 0.003). There was also a correlation between the levels of visfatin and omentin (Rs = 0.3703; p < 0.0001). After the treatment, the omentin levels correlated with the levels of adiponectin (Rs = 0.2705; p = 0.0080), ghrelin (Rs = 0.2121; p = 0.0268), visfatin (Rs = 0.2655; p = 0.0049), and leptin (Rs = 0.2055; p = 0.0032). Moreover, the ghrelin levels correlated negatively with the leptin levels (Rs = 0.3367; p = 0.0003). There was a correlation between the adiponectin and visfatin levels (Rs = 0.3414; p = 0.0006). 3.5. Hormone levels and the percentage of excess weight loss at 50– 54 weeks At 50–54 weeks after treatment, the %EWL less than 25% had 11 patients in the BIB group (11/25; 44.8%). The %EWL less than 50% in
Fig. 1. Median concentration of hormones in relation to the type of treatment. (A). Adiponectin, p value between the levels at baseline and 50–54 weeks: ⁄0.0173; ] 0.0186; § 0.2758. (B). Ghrelin, p value between the levels at baseline and 50–54 weeks: ⁄0.7532; ] 0.0051; § 0.3824. (C). Leptin, p value between the levels at baseline and 50–54 weeks: ⁄ 0.0796; ] <0.0001; § 0.2076. (D). Visfatin, p value between the levels at baseline and 50–54 weeks: ⁄0.1159; ] 0.0457; § 0.9721. (E). Omentin, p value between the levels at baseline and 50–54 weeks: ⁄0.0277; ] 0.9584; § 0.2213. BIB – bioenterics intragastric balloon, LAGB – laparoscopic adjustable gastric banding, SG – sleeve gastrectomy.
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Fig. 2. The leptin levels in relation to the weight loss at 50–54 weeks. (A). Correlation between the leptin concentration and the percentage of total weight loss, %TWL – percentage of total weight loss. (B). The median leptin concentration in relation to the recommended percentage of excess weight lost, %EWL – percentage of excess weight loss.
the surgical groups had 16 patients (16/42; 38.1%) (LABG group: 5 patients, LSG group: 11 patients). Analyzing the levels of hormones between the groups which achieved and did not achieve the recommended threshold of 25% EWL (BIB) or 50% EWL (LAGB, LSG), we found no significant differences in none except the leptin concentration. The patients who achieved recommended %EWL had significantly lower leptin levels at 50–54 weeks than those patients with a lower decrease of %EWL (median: 14.37, IQR: 9.16–28.23 vs 24.85, IQR: 17.29–48.46, p = 0.0182) (Fig. 2B). 4. Discussion Weight reduction induced by bariatric therapies is the most effective strategy for the correction of obesity-associated metabolic and inflammatory alterations. However, the exact mechanism is not well understood. We analyzed the blood profile of hormones in obese patients compared to non-obese patients and the effect of weight loss on their levels following endoscopic and surgical bariatric therapies. Our study showed that the impact of weight reduction on hormonal levels is very complex due to the complexity of hormonal interactions and timeline changes after therapy. We found that the weight loss itself, rather than the procedure type used to reduce body mass, is responsible for the observed hormonal changes, and that the effectiveness of bariatric therapy depend on the size of these changes. Obesity is proposed to be a chronic low-grade inflammatory condition associated with the alteration in the production of several growth factors and pro- and anti-inflammatory cytokines [1,2]. First, we confirmed that obese patients compared to nonobese controls have higher blood levels of leptin and lower levels of ghrelin and adiponectin. We found a negative correlation between the levels of adiponectin and leptin. The chronic subinflammatory state observed in obesity may result from the elevated levels of leptin and decreased levels of adiponectin, and can be responsible for complications, including different types of cancer, as these hormones have opposite effects on cell functions [2–6]. Adiponectin inhibits cell proliferation and the expression of tumor necrosis factor-a (TNF-a), interferon gamma, and interleukin-6 (Il6). It increases Il-10 and tissue inhibitor of metalloproteinases 1 activity by AMP-activated protein kinase (AMPK) signaling [2– 4,25]. Leptin upregulates TNF-a and Il-6, increases insulin resis-
tance, inhibits apoptosis and stimulates cell proliferation, migration and invasion of tumor cells. In turn, Il-6 and TNF-a increase leptin expression in adipose tissue and inhibit adiponectin expression [2–6]. There can be also a crosstalk between the levels of leptin and adiponectin. One study assessed the mechanism of protective effect of adiponectin on vascular extracellular matrix (ECM) remodeling and suggested that adiponectin disrupts the leptin-induced vascular ECM remodeling via adiponectin receptor 1 and enhanced AMPK signaling in endothelial cells, which in turn, promotes SOCS3 up-regulation in smooth muscle cells to inhibit phosphorylation of STAT3 simulated by leptin [26]. More importantly, we observed a significant decrease in the blood levels of leptin and an increase of the adiponectin levels at 50–54 weeks after treatment compared to their baseline values. Moreover, the changes in their levels correlated with %TWL. These observations can explain the positive effect of weight loss on complications by the regulation of adiponectin-leptin imbalance. Additionally, we analyzed the visfatin levels that can be a missing link between endocrine metabolic disorders and immunity. However, data are conflicting [6,9,14,15,25]. Visfatin is produced by visceral adipose tissue and is known as a pre-B cell colonyenhancing factor that mediates inflammatory response by induction of Il-6 and TNF-a, but its higher concentration augments the expression of anti-inflammatory cytokines such as Il-10 [6,9,27]. In comparison to non-obese patients, we observed lower visfatin levels in obese patients which were significantly higher at 50– 54 weeks after treatment compared to their baseline levels. However, its levels did not correlate with weight loss. This supports other authors’ observations that visfatin levels tend to be increased with weight loss [9,14]. We found a positive correlation of its levels with the adiponectin and omentin levels before and after therapy. Visfatin seems to have more complex functions and the explanation for its increase after weight loss is unclear. It may play a role in improving insulin sensitivity after weight loss as it is an insulinmimetic factor [9]. We confirmed that obese patients had decreased omentin levels compared to non-obese patients and that its levels correlated negatively with the leptin levels [7,17]. In contrast to other studies [18,28], weight reduction did not significantly affect its blood levels. The beneficial effects of omentin can be explained by the observation that treatment with omentin led to the relaxation of endothelial cells, increased phosphorylation of
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nitric oxide synthase and AMPK, reduction of cyclooxygenase-2 expression and TNF-a-induced activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-jb) [29]. As it was described above, we found several correlations between levels of tested hormones, before and after treatment. The interactions between all circulating and local factors contribute to obesity and its complications, and dictate the effectiveness of weight loss therapies. In our study, in patients who achieved the recommended %EWL the final leptin concentration was lower than in patients with lower %EWL. The baseline body weight between the both groups of patients was similar. The measurement of the leptin concentration may be helpful to determine which patients will have the greatest benefits from bariatric therapies. The question arises from this observation – whatever patients with insufficient weight loss have increased risk of complications due to higher leptin levels. Different types of bariatric therapies are used for reducing weight with various efficacy [9–12,18,24,30–33]. As we expected, the highest weight loss was observed after LSG and the lowest after BIB therapy. Although the BIB therapy was effective in reducing the body weight within the first 6 months in all patients, its efficacy decreased within the months following the balloon’s removal – only in this group a slight weight gain from its nadir value was observed in 48% of patients, and 8 patients (32%) were referred for bariatric surgery (unpublished results). More importantly, recent data support that weight loss itself and not the manner by which weight loss is achieved is the most important for the correction of obesity-related complications [32]. We also did not report statistically significant differences in the median baseline and final concentrations of hormones between therapies. However, we observed some variations in their levels during the follow-up. The adiponectin levels in the surgical groups increased at all study time points, especially in the LAGB group, but in the BIB group there was a slight decrease at 8–12 weeks followed by an increase at 24– 28 weeks and then a decrease at 50–54 weeks. The leptin levels decreased in all groups at 24–28 weeks and were still decreasing at 50–54 weeks in the surgical groups but not in the BIB group in which we observed the levels increase. Six months after BIB removal, adiponectin and leptin levels tended to gradually return toward baseline. In summary, the timeline changes in hormones levels were the most stable in the groups treated with bariatric surgery, especially in the LSG group. Therefore, the LSG providing the highest weight loss with the smallest hormonal variation over time may be a superior procedure as a first stage of obesity treatment. Our study has some limitations. First, this was a nonrandomized, but prospective and observational study. The number of patients that underwent each bariatric procedure was different. However, the main aim of this study was to analyze the effect of weight loss on the blood levels of hormones, their timeline changes and to assess their correlation with body weight and the amount of weight loss. Further studies with randomization to different procedures would be helpful to better understand the mechanism of weight reduction, although it would be very difficult to perform it. The cooperation with obese patients and monitoring of diet and physical effort during the follow-up is not always reliable. Although it was not the aim of this report to assess the obesityrelated complications and the study duration was too short, we believe that the observed hormonal changes may elucidate well known beneficial long-term effects of weight loss. In conclusion, our study supports previous observations that weight loss itself, rather than the procedure type used to reduce body mass, is responsible for hormonal ameliorations in obese patients. Moreover, the results of this study provide more explanations about the effect of weight loss and bariatric therapies on the hormonal changes in blood and explain, at least in part, why some patients have insufficient weight loss after treatment.
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