Original Article

Decreased Serum S100A10 Levels in Patients with Both and Metabolic Syndrome

Chin-Chuen Lin, M.D., Meng-Chang Tsai, M.D., Tiao-Lai Huang, M.D.* Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

Abstract

Background: Brain-derived neurotrophic factor (BDNF) is involved in the pathophysiology of schizophrenia and metabolic syndrome. S100A10 is associated with the antidepressant effect of BDNF, and decreased S100A10 mRNA has also been found in schizophrenia. S100A10 also interacts with and , both are associated with obesity. In this study, we intended to investigate the serum BDNF and S100A10 levels in patients with schizophrenia with and without metabolic syndrome. Methods: We recruited patients with schizophrenia, collected their demographic data, and measured their metabolic profiles, serum BDNF, and S100A10 levels. Clinical symptoms were evaluated using the Positive and Negative Syndrome Scale. Metabolic syndrome was determined using the criteria provided by the Ministry of Health and Welfare of Taiwan. Results: In this study, 38.7% of 93 participants had metabolic syndrome. No statistical significance was found in serum BDNF levels between patients with and without metabolic syndrome. Patients with metabolic syndrome had significantly lower S100A10 levels compared to those without (p < 0.01). Conclusion: Decreased serum S100A10 levels were found in patients with schizophrenia and metabolic syndrome compared to schizophrenic patients without. Those data suggested that serum S100A10 level could play a rôle in metabolic syndrome among patients with schizophrenia.

Key words: brain-derived neurotrophic factor, energy metabolism, p11, positive and negative syndrome scale Taiwanese Journal of Psychiatry (Taipei) 2020; 34: 110-114

Introduction can be used to help identify individuals at risk of cardiovascular disease [10]. The prevalence of metabolic syndrome in patients Schizophrenia is a multifactorial disorder that involves with schizophrenia is about 35% in males and 50% in females, many pathways. Brain-derived neurotrophic factor (BDNF) both far greater than general population [11]. Many factors is involved in the growth, survival, differentiation, and such as the use of antipsychotic medications, lifestyle, social repair of neurons [1] and is found to be associated with economic status, and genetics, contribute to the increased neuropsychiatric disorders, such as schizophrenia and prevalence of metabolic syndrome among patients with disorder [2]. S100A10, also known as p11, is a schizophrenia [12]. member of the S100 family of calcium effector [3]. Several members of S100 proteins are associated Antidepressant effect of BDNF has been shown to be closely with metabolic syndromes. In the rat model of metabolic related to S100A10 in primary neuronal cultures and syndrome, S100A3 expression is upregulated through transgenic mice [4]. In the peripheral blood mononuclear microarray [13]. Increased expression of S100A8 is found cell of patients with schizophrenia, S100A10 mRNA levels in the whole blood of Latinos with metabolic syndrome as are higher than the controls [5]. compared to those without [14]. Peripheral serum S100A8, Patients with schizophrenia tend to have higher mortality and shorter lifespan [6, 7]. Cardiovascular disease is found to be a major contributing factor to the increased mortality of patients *Corresponding author. No. 123, Ta-Pei Road, Niao-Sung, Kaohsiung 833, Taiwan. with schizophrenia [8, 9]. The diagnosis of metabolic syndrome E-mail: Tiao-Lai Huang

Received: Apr. 21, 2020 revised: Jun. 19, 2020 accepted: Jun. 22, 2020 date published: Sep. 28, 2020 This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to Access this article online remix, tweak, and build upon the work non-commercially, as long as appropriate credit Quick Response Code: is given and the new creations are licensed under the identical terms. Website: For reprints contact: [email protected] www.e-tjp.org

How to cite this article: Lin CC, Tsai MC, Huang TL. Decreased serum DOI: S100A10 levels in patients with both schizophrenia and metabolic syndrome. 10.4103/TPSY.TPSY_28_20 Taiwan J Psychiatry 2020;34:110-4. © 2020 Taiwanese Journal of Psychiatry (Taipei) | Published by Wolters Kluwer - Medknow

110 © 2020 Taiwanese Journal of Psychiatry (Taipei) | Published by Wolters Kluwer - Medknow Lin, et al.: p11 and metabolic syndrome in schizophrenia

A9, and A12 mRNA levels are closely associated with insulin • iWaist circumference 90 cm in males or 80 cm in resistance and inflammation [15]. Lower serum S100A1 females, or body mass index (BMI) 27 kg/m2 levels and higher serum S100B levels have been found in • Systolic BP 130 mgHg≧ or diastolic BP 85≧ mmHg patients with metabolic syndrome than those in healthy • Fasting blood sugar 110 mg/dL ≧ controls [16, 17]. S100A10 has close interactions • LTG 150 mg/dL≧ ≧ with serotonin receptors and annexin A2. S100A10 increases • LHDL < 40 mg/dL in≧ males or < 50 mg/dL in females. ≧ localization of serotonin 1B (5-HT1B) receptors at the cell Patients were considered to have metabolic syndrome if surface [18]. While CNS serotonin inhibits appetite, peripheral they met three or more of those five criteria. serotonin synthesis is associated with obesity, and inhibition The above criteria were modified from the U.S. National of peripheral serotonin can reduce obesity [19]. In adipose Cholesterol Education Program Adult Treatment Panel III tissues, annexin A2 contributes to glucose and fatty acid (2001). The most notable difference is in the definition of transport [20]. Those data suggest that S100 proteins play a central obesity (waist circumference 100 cm or 40 inches rôle in the energy metabolism. in male or 88 cm or 35 inches in female). In this study, we intended to investigate the relationship ≧ between serum BDNF levels, serum S100A10 levels, and Statistical≧ analysis metabolic syndrome in patients with schizophrenia. We described results as mean ± standard deviation. Chi-square was used to analyze the distribution of metabolic Methods syndrome among male and female samples. Independent t-test and analysis of variance (ANOVA) were used to compare Participants serum BDNF and S100A10 levels between patients with and From July 2016 to June 2018, we recruited patients without metabolic syndrome, as well as demographic data with schizophrenia at the Chang Gung Memorial Hospital. between the two groups. We used Pearson correlation to assess Schizophrenia was diagnosed by a psychiatrist using the the relationship with the associated parameters. criteria of the Diagnostic and Statistical Manual of Mental Data analysis was done using Statistical Package of Social Disorders, Fourth Edition (DSM-IV) [21]. Clinical symptoms Science software version 19 (Chicago, Illinois, U.S.A.). The were evaluated using Positive and Negative Syndrome Scale differences were considered significant ifp -values were smaller (PANSS). We also collected demographic data, blood pressure than 0.05. (BP), and waist circumference. Written informed consent was provided by all participants after the content of the study Results was fully explained. The institutional review board of Chang A total of 93 patients with schizophrenia were recruited, Gung Memorial Hospital approved the study designs (protocol including 41 males and 52 females. Their ages were ranged number = IRB 201600266A3, and date of approval = May from 20.8 to 78.1 years, with the mean of 45.8 ± 11.3 years. 11, 2016; IRB 201600266A3C101, and date of approval Illness duration was ranged from 0.9 to 48.2 years, with the June 29, 2017). mean of 20.4 ± 9.4 years. PANSS scores were ranged from 32 Laboratory data to 131, with the mean of 81.7 ± 27.5. Six (6.5%) patients met zero criteria of metabolic syndrome, Venous blood was drawn from each participant in the 25 (26.9%) met one criteria; 26 (28.0%) met two criteria, 26 morning following a six-hour fast. Serum levels of fasting (28.0%) met three criteria, 7 (7.5%) met four criteria, and blood sugar, triglyceride (TG), and high-density lipoprotein three (3.2%) met all criteria. Overall, 36 (38.7%) patients had cholesterol (HDL) were measured in the hospital laboratory. metabolic syndrome. Among them, 19 of 41 (46.3%) male and Serum BDNF protein levels were measured using a 17 of 52 (32.7%) female patients had metabolic syndrome. commercially available ELISA kit of the sandwich type, i.e., The male and female distribution of metabolic syndrome was BDNF Emax Immunoassay System (Promega Corporation, not significant. Using ATP III criteria, 15 (16.1%) patients Madison, Wisconsin, USA). Each system contained anti-BDNF met zero criteria of metabolic syndrome, 23 (24.7%) met one mAb, Block&Sample 5X buffer, BDNF standard, antihuman criteria, 22 (23.7%) met two criteria, 23 (24.7%) met three BDNF pAb, anti-IgY HRP, TMB solution, peroxidase substrate, criteria, 7 (7.5%) met four criteria, and three (3.2%) met all and protocol. We measured serum S100A10 protein levels with criteria. Overall, 33 (35.5%) patients had metabolic syndrome. a commercially available ELISA kit, i.e., CircuLex S100A10 Using independent t-test, no statistical significance was ELISA Kit (CycLex Company, Ltd., Taipei), which employs found in BDNF levels between patients with and without the quantitative sandwich enzyme immunoassay technique. metabolic syndrome (18.7 ± 6.5 ng/mL vs. 18.4 ± 8.2 ng/mL, All samples were assayed or duplicated by the same senior no significant difference). Using independent t-test, patients laboratory assistant according to the manufacturers’ manuals. with metabolic syndrome had significantly lower S100A10 Criteria of metabolic syndrome levels compared to those without metabolic syndrome Health Promotion Administration of Ministry of Health and (0.2 ± 0.4 ng/mL vs. 0.7 ± 1.5 ng/mL, p < 0.05). Those results Welfare of Taiwan used the following five criteria of metabolic are summarized in Table 1. Among all patients, no significant syndrome in 2004: correlation was found between serum S100A10 levels, serum

Taiwanese Journal of Psychiatry (Taipei) Volume 34, Issue 3, July-September 2020 111 Lin, et al.: p11 and metabolic syndrome in schizophrenia

BDNF levels, age, BMI, and PANSS scores (Pearson’s r values Table 1. Serum brain‑derived neurotrophic factor and are 0.125, 0.102, − 0.074, and 0.144, respectively). Among S100A10 levels in patients with schizophrenia, all patients, serum BDNF protein levels showed significant with and without metabolic syndrome correlation with body weight (p < 0.01) and BMI (p < 0.001). In male patients (n = 41) only, using independent t-test, With metabolic Without metabolic no statistical significance was found in BDNF levels between syndrome (n=36) syndrome (n=57) patients with and without metabolic syndrome (18.2 ± 7.2 ng/mL Age (years) 45.3 ± 10.1 46.2 ± 12.3 vs. 18.0 ± 8.5 ng/mL, no significant significance). In males, Onset (years) 24.6 ± 8.4 26.5 ± 9.2 serum BDNF protein levels showed significant correlation Duration (years) 21.3 ± 9.4 19.8 ± 9.4 2 with BMI (p < 0.05) but not body weight. Using independent BMI (kg/m ) 28.1 ± 4.4 24.7 ± 6.2** t-test, patients with metabolic syndrome had significantly lower PANSS score 85.9 ± 28.0 79.1 ± 27.1 S100A10 levels compared to those without metabolic syndrome BDNF (ng/mL) 18.7 ± 6.5 18.4 ± 8.2 S100A10 (ng/mL) 0.2 ± 0.4 0.7 ± 1.5* (0.1 ± 0.1 ng/mL vs. 1.0 ± 2.0 ng/mL, p < 0.05). *p < 0.05; **p < 0.01, using independent t‑test (n = 94). In female patients (n = 52) only, using independent t-test, BDNF, brain‑derived neurotrophic factor; BMI, body mass index; no significance was found in BDNF levels between patients PANSS, Positive and Negative Syndrome Scale with and without metabolic syndrome (19.3 ± 5.7 ng/mL vs. 18.6 ± 8.2 ng/mL, no significant significance). In females, serum BDNF protein levels showed significant correlation with body weight (p < 0.01) and BMI (p < 0.01). Using independent t-test, patients with metabolic syndrome had no significantly different S100A10 levels compared to those without metabolic syndrome (0.3 ± 0.5 ng/mL vs. 0.5 ± 1.1 ng/mL, no significant difference). Using two-way ANOVA adjusted with sex and metabolic syndrome, no significance was found in S100A10 levels. In patients without metabolic syndrome, serum BDNF protein levels showed significant correlation with body BMI (p < 0.01). Among patients without metabolic syndrome, S100A10 levels were not significantly different between males and females. In patients with metabolic syndrome, serum BDNF protein levels showed significant correlation with body BMI (p < 0.01). Among patients without metabolic syndrome, Figure 1. S100A10 distribution of males and females with and without males had significantly lower S100A10 levels p( < 0.05). metabolic syndrome. The distributions of S100A10 of males and females with and without metabolic syndrome (Figure 1). promoter regions [23]. The underlying mechanism of S100A10 in schizophrenia is unclear, but several possibilities exist. Discussion S100A10 can increase the localization of serotonin receptors As shown in Table 1, the major finding of this study at the cell surface [18] and serotonin dysfunction has also been was significantly decreased (p < 0.05) serum S100A10 associated with schizophrenia. Another theory involves the levels in schizophrenic patients with metabolic syndrome increased phsoplipase A2 (PLA2) in schizophrenia [24, 25]. (0.2 ± 0.4 ng/mL) compared to schizophrenic patients without S100A10 has been found to inhibit the activity of PLA2, so a (0.7 ± 1.5 ng/mL). A few studies existed to investigate decreased level of S100A10 may contribute to the increased S100A10 in the past, and their findings are not easily PLA2 levels in schizophrenia [26]. comparable due to methodology differences. In patients In S100A10 and metabolic syndrome, we found no direct with schizophrenia, major depressive disorder, and bipolar reference. Several S100 family proteins, such as S100A1, disorder, higher S100A10 mRNA levels are found compared to those of healthy controls [5]. Comparison of whole-genome A3, A8, A9, A12, and B, are associated with metabolic profiles using microarrays on LCLs from syndrome [13-17]. In the male Zucker Diabetic Fatty rat 413 patients with schizophrenia and 446 controls has shown model of metabolic syndrome, microarray for 14921 decreased expression of S100A10 in the patients [22]. In a have revealed 36 genes with up-regulation and 49 genes study investigating SNPs and abnormal eye movements in with down-regulation, as compared to those of lean controls, patients with schizophrenia, 16 SNPs are found relevant to and S100A3 gene is among the up-regulated genes [13]. the horizontal position gain during the fast Lissajous paradigm Whole blood gene microarray of 74 Latinos with metabolic of the smooth pursuit test; 10 SNPs at 1q21.3 are located in syndrome, and 110 counterparts without has shown increased intron or intergenic regions of the THEM4 or S100A10 genes, expression of S100A8 in those with metabolic syndrome and further analysis suggests that those are in the enhancer or [14]. Peripheral blood S100A8, A9, and A12 mRNA

112 Taiwanese Journal of Psychiatry (Taipei) Volume 34, Issue 3, July-September 2020 Lin, et al.: p11 and metabolic syndrome in schizophrenia levels are closely associated with insulin resistance and • The study had a cross sectional design, without longitudinal inflammation [15]. A study has shown lower serum S100A1 follow-up, limiting the data interpretation. levels in the metabolic syndrome group than the controls [16]. Another study has shown higher S100B protein levels in the Summary metabolic syndrome group than the controls [17]. While no Decreased serum S100A10 levels were found in patients direct reports of S100A10 have been found, S100A10 have with schizophrenia with metabolic syndrome compared to been known to interact closely with serotonin and annexin A2, those without. Those data suggest that S100A10 could play a two molecules closely related to obesity. Global activation of rôle in metabolic syndrome among patients with schizophrenia. central serotonin system suppresses feeding [27] but peripheral serotonin acts as a factor that enhances nutrient absorption and Acknowledgment storage [28]. In mice, the inhibition of peripheral serotonin synthesis can promote brown adipose tissue thermogenesis, CC Lin, MC Tsai, and TL Huang all contributed to the leading to reduction of obesity [19]. Annexin A2, responsible design and writing of this paper. for endosomal regulations, contributes to glucose and fatty acid transport [20]. Silencing of annexin A2 improves insulin Financial Support and Sponsorship sensitivity and glucose uptake [29]. S100A10 can influence This work was supported by clinical research grants metabolic syndrome through the interactions of those CMRPG8F0631 and CMRPG8F0632, from Kaohsiung Chang molecules. Gung Memorial Hospital in Taiwan. We found no significant difference in serum BDNF levels between schizophrenic patients with and without metabolic Conflicts of interest syndrome (Table 1). But we found that BDNF levels were None. significantly correlated with BMI p( < 0.001) and body weight (p < 0.01). This discrepancy of findings can be caused by the References fact that some criteria of metabolic syndrome are not influenced 1. Lewin GR, Barde YA: Physiology of the neurotrophins. Annu Rev by BDNF pathway. Previously, we also have not noticed Neurosci 1996; 19: 289-317. a difference until male and female patients were analyzed 2. Thompson Ray M, Weickert CS, Wyatt E, et al.: Decreased BDNF, trkB- separately [30]. Another study reports no differences in serum TK+ and GAD67 mRNA expression in the hippocampus of individuals with schizophrenia and mood disorders. J Psychiatry Neurosci 2011; 36: BDNF levels between patients with schizophrenia and BMI 195-203. matched controls [31]. Many studies report that BDNF can 3. 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Capasso RM, Lineberry TW, Bostwick JM, et al.: Mortality in found nothing significant. This finding is different from those schizophrenia and schizoaffective disorder: an Olmsted County, earlier findings. We also found that in male patients, those with Minnesota cohort: 1950-2005. Schizophr Res 2008; 98: 287-94. metabolic syndrome had significantly lower S100A10 levels 7. Saha S, Chant D, McGrath J: A systematic review of mortality in schizophrenia: is the differential mortality gap worsening over time? than those without, but the phenomenon could not be found Arch Genl Psychiatry 2007; 64: 1123-31. in females. Whether S100A10 behaves differently according 8. Laursen TM: Life expectancy among persons with schizophrenia or to gender requires further investigation to confirm. bipolar affective disorder.Schizophr Res 2011; 131: 101-4. The prevalence of metabolic syndrome of the study sample 9. 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