Objective: Spexin (SPX) is a novel peptide implicated in food intake and satiety. SPX levels are reduced in obese patients. Aim: This study aimed to compare serum SPX levels in obese adolescents versus healthy controls and to assess the associations of metabolic syndrome (metS) antecedents with serum SPX levels. Methods: Eighty consecutive obese adolescents aged 10–18 years and 80 healthy peers were enrolled. Anthropometric measurements, pubertal examinations, and clinical blood pressure measurements were performed. Fasting blood samples were drawn for glucose, insulin, lipids, uric acid, alanine aminotransferase (ALT), and SPX. metS was diagnosed using International Diabetes Federation criteria. Associations of serum SPX with clinical and laboratory variables were assessed. Results: Obese adolescents had lower serum SPX levels than healthy peers (50 pg/mL [25–75% IQR: 25–98 pg/mL] and 67.0 pg/mL [25–75% IQR: 32.5–126.0 pg/mL]; respectively, p = 0.035). Twenty (25%) obese adolescents were diagnosed as having metS. Obese adolescents with metS had lower SPX than those without metS (24.5 pg/mL [25–75% IQR: 15.3–49.5 pg/mL] and 69.0 pg/mL [25–75% IQR: 42.0–142.0 pg/mL]; respectively, p < 0.0001). The frequencies of hyperuricemia, IR, and elevated ALT were similar in obese adolescents with metS and those without metS (p > 0.05 for all). Serum uric acid levels were correlated significantly with serum SPX after correcting for BMI and HOMA-IR (r = −0.41, p < 0.05). A serum SPX level at a cutoff level of 49.5 pg/mL predicted the presence of metS in obese adolescents with 75% sensitivity and 71% specificity. Conclusions: Obese adolescents have reduced SPX levels, and this reduction is more pronounced in those with metS. Further research is needed to verify the utility of SPX as a biomarker in the diagnosis of metS in obese adolescents.

Childhood obesity is a global public health issue with increasing prevalence. Obesity is associated with a number of adverse health consequences including type 2 diabetes, dyslipidemia, and hypertension [1, 2]. It is worrisome that children have started developing diseases traditionally considered as restricted to adulthood [3]. In addition, the relationship between adolescent obesity and adulthood obesity is well established [4]. For these reasons, it is imperative to identify children with overweight and obesity and to investigate the obesity-related risk factors and biomarkers in children in detail, so that timely counseling and treatment can be provided.

Metabolic syndrome (metS) is a combination of increased adiposity, insulin resistance (IR), increased blood pressure (BP), and dyslipidemia, leading to many complications including chronic low-grade inflammation, oxidative stress, hyperuricemia, and nonalcoholic fatty liver disease besides diabetes and cardiovascular disease [5‒9]. The prevalence of metS is rising tremendously in the younger population [1, 2]. It is important to identify the metS-related indicators in obese children and adolescents to prevent future cardiovascular disease.

Adipose tissue not only serves as a site for energy storage but also secretes a variety of adipokines [10, 11]. Some of these adipokines influence weight via their effect on satiety, hunger, glucose, and lipid metabolism [12, 13]. Spexin (SPX) is a novel peptide discovered in 2007 using Markov modeling [14]. Previous studies have demonstrated expression of SPX mRNA and protein in several tissues, especially in the gut, endocrine organs, and visceral fat [15, 16]. Walewski et al. [17] reported that the gene encoding SPX was the most downregulated gene in obese omental and subcutaneous human adipose tissue. Although the physiological significance of SPX remains mostly unclear, results from preliminary studies indicate its potential roles in regulation of obesity, energy homeostasis, appetite control, and glucose and lipid metabolism [18]. The objective of the current study was to determine serum SPX concentrations in normal weight versus obese adolescents and to evaluate the potential associations of metS antecedents with serum SPX levels in obese adolescents.

Subjects and Design

A total of 160 adolescents (80 consecutive obese patients and 80 healthy peers) aged 10–18 years were evaluated in this single-center, prospective, cross-sectional study. For an effect size of 0.40, 80 subjects were considered sufficient for each group with a power of 90% (beta) at a p level of <0.05. The study was conducted in the Pediatric Endocrinology Outpatient Clinic at the Sisli Hamidiye Etfal Health Practices and Research Center. The participants were considered obese if their BMI was ≥2 standard deviation scores (SDSs). BMI SDS was calculated according to the CDC data [19].

In order to comprise an age- and gender-matched healthy control group for the obese adolescents, a list of a random sample of children was obtained from the Well Child Care Unit register. Phone calls were made to the families of the healthy adolescents in the list by order sampling in each age group, to yield a matched control group for the obese adolescents. Approximately 70% of the controls invited by phone calls were willing to participate. The cutoff level for BMI SDS in the control group to exclude overweight adolescents was 1.3 SD [20].

Tanner staging was used in the evaluation of pubertal status [21]. In all participants, pubertal status was between Tanner stage 2 and 5.

A comprehensive medical assessment was performed, and a thorough medical history was obtained for all subjects. All the enrollees were born at term with a weight appropriate for gestational age, had no chronic disease or syndromic disorder, and were not using any medication (including oral or inhaled corticosteroids). The study protocol was approved by the local ethics committee (No. 2479), and an informed consent for participation in the study according to the recommendations of the Declaration of Helsinki on Biomedical Research Involving Human Studies was obtained from all the adolescents and their parents or legal guardians.

Clinical Measurements

The height, weight, and waist circumference (WC) values were measured with light clothing, without shoes, using a Harpenden stadiometer (Holtain Limited, Crymych, UK), an electronic scale (measured to the nearest 0.1 kg), and a nonstretchable fiber measuring tape after a 12-h overnight fast, and recorded to the nearest 0.1 cm. WC was measured midway between the lowest rib margin and the iliac crest, in a horizontal plane at the end of the expirium. SDSs of the anthropometric measurements were calculated according to the CDC data [19]. The percentiles for WC were calculated according to the national data [22]. Diastolic and systolic BP (mm Hg) measurements were performed using a mercury sphygmomanometer, and the measurements were repeated twice in a sitting position after 20 min of rest, using a cuff appropriate for body size, and the average measurement was recorded. The SDSs of the clinical BP measurements were calculated [23].

Laboratory Tests

All of the participants had a venous blood sample collected following an overnight 12-h fast to assess SPX, glucose, insulin, lipid profile, uric acid, and alanine aminotransferase (ALT). The centrifuged blood samples were stored at −80°C until analysis. In healthy adolescents, only serum SPX levels were analyzed due to ethical issues owing to lack of standardized normative data for this variable.

SPX was measured using a specific enzyme linked immunoassay. The intra-assay and interassay coefficients of variation for SPX were 5.59% and 5.50%, respectively. Serum total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride levels were measured by the Friedewald method, glucose was measured by the oxidase method, and insulin was measured by the radio immune assay method (intra-assay CV: ≤3.99% – interassay CV: ≤4.8%). Serum ALT was measured by the spectrophotometric method, and uric acid was measured by the enzymatic colorimetric method using Roche Diagnostics Cobas Integra 800.

Obese adolescents with metS were diagnosed according to the International Diabetes Federation (IDF) guidelines. In adolescents aged 10–16 years, metS was diagnosed in presence of abdominal obesity (WC ≥90th percentile) and 2 or more other clinical features (triglyceride ≥150 mg/dL [1.7 mmol/L], HDL-cholesterol <40 mg/dL [1.03 mmol/L], systolic BP ≥130 mm Hg and/or diastolic BP ≥85 mm Hg, and fasting blood glucose ≥100 mg/dL [5.6 mmol/L]). In patients older than 16 years, adult IDF criteria were used [24].

Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated using the following formula [25]: HOMA-IR = (fasting insulin [μIU/mL] × fasting glucose [mmol/L])/22.5. A HOMA-IR value >3.16 was used in the puberty, and a value >2.5 was used in the postpubertal period to define IR [26, 27]. Elevated levels of serum ALT were defined as levels >the 97th percentile for age and sex according to the charts published by Bussler et al. [28]. Likewise, hyperuricemia was defined as a serum uric acid value ≥the 75th percentile adjusted for age and sex as described elsewhere [29].

Statistical Analysis

SPSS 15.0 for Windows and GraphPad Prism 9 programs were used for the statistical analysis. The normality of the variables was tested by the D’Agostino-Omnibus Pearson normality test. Quantitative variables were summarized as mean (SD) or median (interquartile range [IQR]: 25–75%), depending on the distributions of the variables. A 2-tailed t test or a Mann-Whitney U test was used for intergroup comparison to compare quantitative variables, depending on the normality of the variables. Categorical variables were summarized by number and percentage of the patients. Depending on distributions of the variables, Spearman rank correlation or Pearson correlation coefficient was used as appropriate. Because BMI, WC, serum SPX, and triglyceride levels were not normally distributed, they were normalized using GraphPad Prism 9 prior to multivariate regression analysis. Multivariable regression analysis was used to examine the independent factors associated with serum SPX levels. The receiver operating characteristics (ROC) curve was used to assess the ability of serum SPX to predict the presence of metS in obese subjects. The optimal cutoff value was determined for serum SPX for the diagnosis of metS, and the area under the ROC curve for the sensitivity and specificity of serum SPX was calculated. The ‘“best fit”’ value of the curve (the threshold value for which [sensitivity + specificity − 100] is maximized) was determined using the Youden index. The results are presented with 95% CIs. Two-tailed significance was granted for a p value of p ≤ 0.05.

Demographic Variables

The demographic characteristics of the participants are outlined in Table 1. The mean birth weight of the obese adolescents was lower than that of controls (p = 0.02). The obese adolescents had a significantly higher frequency of family history of obesity, hypertension, coronary artery disease, or type 2 diabetes in their first-degree relatives compared to the healthy peers (p < 0.001).

Table 1.

Comparative analyses of demographic data, clinical data, and serum SPX levels in obese adolescents versus healthy controls

 Comparative analyses of demographic data, clinical data, and serum SPX levels in obese adolescents versus healthy controls
 Comparative analyses of demographic data, clinical data, and serum SPX levels in obese adolescents versus healthy controls

Clinical Variables

The clinical characteristics of obese adolescents and controls are shown in Table 1. As expected, the BMI, BMI SDS, and WC values were found to be higher in the obese adolescents. The obese adolescents also had higher systolic and diastolic BP SDS values (p < 0.001). Thirteen (16.2%) obese adolescents had systolic and/or diastolic hypertension. BP measurements were within the normal range in the controls, as expected. Comparison of serum SPX levels between the obese adolescents and healthy peers revealed lower SPX levels in the obese adolescents (Table 1; Fig. 1).

Fig. 1.

Serum SPX levels in obese adolescents versus healthy peers (*p< 0.05).

Fig. 1.

Serum SPX levels in obese adolescents versus healthy peers (*p< 0.05).

Close modal

Metabolic Characteristics of Obese Adolescents

Fasting hyperglycemia was found in 13.8% (n = 11) of the obese adolescents. Forty-two (52.5%) obese adolescents had IR as assessed by HOMA-IR. Eleven (13.8%) obese adolescents had elevated serum triglyceride levels, 18 (22.5%) obese adolescents had reduced serum HDL-C levels, and 8 (10%) obese adolescents had both elevated serum triglycerides and reduced serum HDL-C levels. metS was diagnosed in 20 (25%) adolescents. Serum uric acid levels were elevated in 14 (17.5%) obese adolescents, and 24 (30%) obese adolescents had elevated serum ALT levels.

Comparison of Clinical and Metabolic Variables and Serum Spexin Levels between Obese Adolescents with metS+ and Those without metS

The comparative analyses of the clinical and laboratory variables between the obese adolescents with metS (n = 20) and those without metS (n = 60) are depicted in Table 2. The obese adolescents with metS were older than those without metS, but the difference was not significant (p = 0.07). The pubertal states and BMI SDS values of the metS+ and metS− obesity subgroups were not different (p > 0.05 for all). The obese adolescents with metS+ had higher systolic and diastolic BP SDS values (p = 0.001 and p = 0.003, respectively). The obese adolescents with metS had lower serum SPX levels than those without metS (p < 0.001). Moreover, serum uric acid levels and HOMA-IR values were significantly higher in the obese adolescents with metS than those without metS (p < 0.05). Nevertheless, the frequencies of hyperuricemia and IR were similar between the obesity subgroups. Serum ALT levels and the frequencies of hypertransaminasemia were not different between the obesity subgroups (p > 0.05 for all).

Table 2.

Comparative analyses of clinical data, metabolic variables, and serum SPX levels in metS+ versus metS− obesity subgroups

 Comparative analyses of clinical data, metabolic variables, and serum SPX levels in metS+ versus metS− obesity subgroups
 Comparative analyses of clinical data, metabolic variables, and serum SPX levels in metS+ versus metS− obesity subgroups

Correlation Analyses of Serum Spexin with Clinical and Laboratory Variables

Serum SPX levels in the study population were correlated with weight SDS (r = −0.16, p = 0.004), BMI SDS (r = −0.24, p = 0.003), and WC (r = −0.19, p = 0.02). Correlation analyses of serum SPX levels with age, birth weight, BP, and pubertal staging did not reach significance (p > 0.05 for all) (Table 3).

Table 3.

Correlation analyses of SPX with chronological age, birth weight, and clinical variables in the study population (n = 160) and with laboratory-related variables in obese adolescents (n = 80)

 Correlation analyses of SPX with chronological age, birth weight, and clinical variables in the study population (n = 160) and with laboratory-related variables in obese adolescents (n = 80)
 Correlation analyses of SPX with chronological age, birth weight, and clinical variables in the study population (n = 160) and with laboratory-related variables in obese adolescents (n = 80)

In the obese adolescents, the correlation analyses of serum SPX levels with metabolic variables revealed that SPX was correlated with insulin (r = −0.3, p = 0.007), log-HOMA-IR (r = −0.32, p = 0.009), total cholesterol (r = −0.48, p = 0.016), HDL-C (r = +0.24, p = 0.03), uric acid (r = −0.46, p = 0.0003), and ALT (r = −0.24, p = 0.03). The correlations of serum uric acid with serum SPX remained significant after adjusting for BMI SDS and log-HOMA-IR (r = −0.41, p = 0.001). Correlations of serum SPX with glucose, LDL-C, and triglycerides did not reach significance (p > 0.05, for all) (Table 3). Overall, when the putative influencing factors associated with serum SPX levels in obese adolescents were assessed using backward stepwise regression analysis (the entered variables: BMI SDS, log-HOMA-IR, and log-ALT), serum uric acid emerged as the most significant variable associated with serum SPX (R2 = 0.21, β = −0.457, p < 0.001) (Table 4).

Table 4.

Backward stepwise regression analysis of factors associated with serum SPX levels in obese adolescents (Nagelkerke’s R2 = 0.21)

 Backward stepwise regression analysis of factors associated with serum SPX levels in obese adolescents (Nagelkerke’s R2 = 0.21)
 Backward stepwise regression analysis of factors associated with serum SPX levels in obese adolescents (Nagelkerke’s R2 = 0.21)

The ROC curve analysis revealed that serum SPX levels predicted the presence of metS in obese adolescents. A serum SPX level at a cutoff of level of 49.5 pg/mL predicted the presence of metS in obese adolescents with a sensitivity of 75% and a specificity of 71% (Fig. 2).

Fig. 2.

ROC curve of serum SPX to predict the presence of metS in obese adolescents. Area under the ROC curve: 0.81 (95% CI: 0.69–0.90, p< 0.001).

Fig. 2.

ROC curve of serum SPX to predict the presence of metS in obese adolescents. Area under the ROC curve: 0.81 (95% CI: 0.69–0.90, p< 0.001).

Close modal

In the current study, we found reduced serum SPX levels in obese adolescents when compared with healthy peers, as has been shown previously [30, 31]. In addition, we found that the reduction in SPX levels was more pronounced in obese adolescents with metS. Furthermore, we showed that a cutoff value of serum SPX below 49.5 pg/mL could predict metS in obese adolescents with a sensitivity of 75% and a specificity of 71%. Among the surrogates of metS, serum uric acid emerged as the variable that was more strongly associated with serum SPX levels compared to the other variables tested in the study.

Being born SGA was an exclusion criterion in the current study as this is associated with adverse long-term health sequelae such as hypertension, coronary heart disease, dyslipidemia, visceral obesity, impaired glucose tolerance, and type 2 diabetes [32, 33]. In the current study, the BW SDSs of the adolescents were lower than that of the healthy controls. Yet, none of the subjects were born SGA or LGA.

metS is an entity that is more directly related to cardiovascular risk than obesity [34, 35]. That is why there is immense research on identifying the precise definition of metS and its antecedents in children and adolescents. To this end, several criteria have been developed, all with some caveats [36, 37]. IR has been considered a major component of metS [37]. However, the current definition of metS in adolescents does not include IR as a diagnostic criterion [24]. We also assessed glucoinsulinemic markers, serum uric acid, and ALT in our obese patients in addition to the standard biochemical workup to have a more in-depth insight on the current metabolic status of the patients [38]. In the current study, 25% of the obese adolescents were diagnosed as having metS and 52.5% had IR as assessed by HOMA-IR. Although HOMA-IR levels were higher in the patients with metS, the frequency of IR was similar between the groups. Dyslipidemia is also central in the development of cardiovascular events and atherosclerosis. In our study, 26.3% of the obese adolescents had dyslipidemia. One of the comorbidities of obesity that is not covered in the current definitions of metS in adolescents is nonalcoholic hepatosteatosis. Serum ALT has long been used as a surrogate marker of hepatosteatosis [28]. In a study, conducted on overweight and obese children, it was found that increased serum ALT levels were highly prevalent and associated with metS [39]. In our study, 30% of the obese adolescents had hypertransaminasemia. However, the frequency of hypertransaminasemia did not differ when we compared the adolescents with and without metS. Nevertheless, it should be kept in mind that normal serum ALT levels do not rule out hepatosteatosis. Uric acid is one of the surrogates of metS that has been shown to be associated with poor metabolic outcome. Serum uric acid levels within the normal ranges have antioxidant and endothelial protective effects. However, at increased concentrations, uric acid may act as a pro-oxidant that increases cardiovascular risk [40]. In the current study, we found that obese adolescents with metS had higher uric acid levels than those without metS. However, the frequency of hyperuricemia was similar in the obesity subgroups. This lack of difference between the groups could possibly be due to the relatively lower number of the obese adolescents with metS.

In the current study, we found reduced SPX levels in obese adolescents, and as expected, SPX had a negative correlation with BMI and WC. It is known that central distribution of fat or increase in the adiposity is associated with a decline in serum SPX levels. Lin et al. [41] indicated that serum SPX levels were correlated with BMI and concluded that SPX levels could predict the risk of high BMI. One of the novel aspects of the current study is that the reduction in serum SPX levels was more pronounced in obese adolescents with metS than in those without metS. Moreover, we found that SPX may serve as a moderately sensitive predictor of metS. In the literature, there are conflicting data about the relationship between metS and SPX levels. Al-Daghri et al. [42] reported that serum SPX levels were significantly lower in adult patients with metS compared to the ones without metS. However, stratification based on sex showed that SPX was associated with metS only in females. On the other hand, no correlation was found between serum SPX levels and development of metS in another adult study [43]. Recently, Behrooz et al. [44] investigated the association of serum SPX levels with metS in children. They found no significant difference in SPX levels among children with higher TG, higher fasting blood glucose, higher systolic BP, larger WC, lower HDL, and children with IR and hyperinsulinemia in comparison with children who had values within the normal range for these factors. They reported that children with metS had lower SPX levels in comparison with children without metS, but this difference was not statistically significant. However, this may be due to the small number of subjects in the subgroups [44]. In the current study, we also evaluated the associations between serum SPX levels and metabolic variables. We found that serum SPX was negatively correlated with insulin, HOMA-IR, uric acid, total cholesterol, and ALT and positively correlated with HDL-C, but there was no correlation with glucose, triglyceride, and LDL-C levels. Among the variables tested, uric acid was found to have the most significant negative association with SPX levels, a finding that persisted even after correction for BMI and IR. To our knowledge, this is the first study investigating and documenting association of serum SPX with uric acid. Longitudinal studies are needed to confirm the significance of this association. However, Said et al. [45] demonstrated that SPX injection alleviated hyperuricemia in rats with high-fructose diet-induced metS, supporting our finding.

In line with our findings, Chen et al. [46] reported that SPX levels had inverse correlations with fasting insulin and HOMA-IR in prepubertal obese children, and they also found a negative correlation between SPX and triglyceride levels in contrast to our study. On the other hand, Kumar et al. [30] did not find a relationship between SPX and glycemic variables (fasting glucose and insulin) in obese children. Hodges et al. [47] evaluated the effects of obesity and type 2 DM on SPX levels in adolescents. They found that SPX was not significantly altered by obesity or diabetes, nor was there a correlation with insulin sensitivity or lipid profile. Controversial results were also present in adult studies investigating the relationship between SPX and glycemic variables [48‒50]. However, it was shown that SPX treatment reduced body weight and improved glucose tolerance by reducing IR and HbA1c in obese mice with type 2 DM [51]. In the current study, we revealed that SPX had a positive correlation with total cholesterol and a negative correlation with HDL. However, we did not find any correlation between SPX and LDL-C and TG. Controversial results have also been reported regarding the role of SPX in lipid metabolism in the literature [16, 41, 42, 46‒48]. Khadir et al. [52] reported strong negative correlations with fasting plasma lipids, such as LDL-C, TG, and TC and positive correlation with HDL-C. In a study carried out on adult patients with metS, it was shown that SPX levels were negatively correlated with TG levels and positively correlated with HDL-C levels [42]. Hodges et al. [47] reported that SPX was not significantly correlated with lipid profile (TC, HDL-C, LDL-C, TG, and nonesterified fatty acids) or total fat mass in adolescents. Karaca et al. [48] also failed to find any correlation between SPX levels and lipid levels in diabetic patients. The available literature does not concretely indicate a significant correlation of SPX with the aforementioned variables. The differences regarding correlation coefficients in different studies remain to be determined. However, increased appetite and high serum glucose, cholesterol, and TG levels were demonstrated in SPX knockout zebrafish, thus suggesting the role of this peptide in the regulation of satiety as well as glucose and fat metabolism [53]. Moreover, SPX injection significantly reduced TC, LDL-C, and TG and significantly increased HDL-C in rats with high-fructose-induced metS [45].

In a mouse model with hepatosteatosis, SPX treatment efficiently reduced hepatic lipid levels by reducing fatty acid uptake into hepatocytes [51]. In line with this finding, we found a significant negative correlation between serum SPX and ALT levels.

The strength of the study was the fact that we assessed obese adolescents and healthy peers living in the same geographic area with similar socioeconomic states to reduce bias related to the demographic characteristics of the subjects. Moreover, we reported significant associations of serum SPX with metS antecedents in pediatric obese patients. We may also suggest that serum SPX may be a moderately sensitive biomarker of metS in obese adolescents.

Our study has some limitations. The design of the study prevents making hard end point conclusions as is the case in every cross-sectional study. Moreover, we did not assess the dietary and exercise status of the subjects, which might have an impact on SPX levels. Behrooz et al. [44] reported that there was a significant negative association between total dietary fat intake and SPX. It has also been shown that SPX levels increase significantly in response to physical exercise [52]. The association of serum SPX with baseline laboratory variables might have changed, if more dynamic tests such as OGTT were performed. Nevertheless, the design of the study allowed us to compare our data with other studies performed in line with the current study.

Obese adolescents have reduced SPX levels, and this reduction is more pronounced in those with metS. The utility of serum SPX as a biomarker of metS in obese adolescents awaits further studies.

Subjects (or their parents or guardians) have given their written informed consent to publish their case (including publication of images). The study was conducted according to the principles of the Declaration of Helsinki and approved by the institutional ethical review board (Approved No. 2479).

There are no competing interests to declare.

This study was funded by the Scientific Research Funding by the University of Health Sciences, Project No. 2020-20.

All authors have read and approved the final manuscript. Nida Gulderen Kalay Senturk, Aydilek Dagdeviren Cakir, Zeynep Yıldız Yıldırmak, and Ahmet Uçar performed research. Nida Gulderen Kalay Senturk, Zeynep Yıldız Yıldırmak, and Ahmet Uçar designed the research. Nida Gulderen Kalay Senturk and Ahmet Uçar analyzed the data. Nida Gulderen Kalay Senturk, Aydilek Dagdeviren Cakir, and Ahmet Ucar wrote the manuscript.

All data generated or analyzed during this study are included in this article.

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