ORIGINAL RESEARCH published: 08 July 2022 doi: 10.3389/fendo.2022.909201 New Insights in Cytokines in Childhood Obesity: Changes in TWEAK and CD163 After a 2-Year Intervention Program in Prepubertal Children With Obesity Rocı́o Escartı́n 1, Maria Font 1, José Miguel González-Clemente 2, Joan Vendrell 3,4, Edited by: Assumpta Caixàs 2 and Raquel Corripio 1* Iwona Ben-Skowronek, Medical University of Lublin, Poland 1Pediatric Endocrine Department, Hospital Universitari Parc Taulı´, Institut d’Investigació i Innovació Parc Taulı´, Universitat Reviewed by: Autònoma de Barcelona, Sabadell, Spain, 2 Endocrinology and Nutrition Department, Hospital Universitari Parc Taulı´, Institut Malgorzata Wojcik, d’Investigació i Innovació Parc Taulı´, Universitat Autònoma de Barcelona, Sabadell, Spain, 3 Endocrinology and Diabetes Jagiellonian University Medical Unit, Research Department, Hospital Universitari Joan XXIII de Tarragona, Institut Pere Virgili, Tarragona, Spain, 4 CIBER de College, Poland Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain Isolina Riaño Galan, Central University Hospital of Asturias, Spain Objective: Obesity is characterized by a low-grade inflammatory state in adipose tissue. Meritxell Torrabı´as Rodas, Tumor Necrosis Factor Weak Inducer of Apoptosis (TWEAK) and Cluster of Differentiation Hospital Universitari de Vic, Spain 163 (CD163) are cytokines potentially involved in the pathogenesis of obesity. Little is Dominika Janus, Jagiellonian University Medical known about them in children. The aim of this study was to observe serum levels of College, Poland TWEAK and CD163 in prepubertal children with obesity compared to lean, and to evaluate *Correspondence: its changes after a 2-year intervention program in children with obesity. Raquel Corripio raquelcorripio@gmail.com; Methods: Case-control study with a prospective follow-up of cases for 2 years in a rcorripio@tauli.cat referral pediatric endocrine outpatient centre. Seventy-three prepubertal children with obesity, and forty-seven age- and gender-matched lean controls were studied. Sixty-two Specialty section: This article was submitted to cases finished the program. Anthropometric parameters, Homeostatic Model Pediatric Endocrinology, Assessment for Insulin Resistance (HOMA-IR), lipid profile, and concentrations of a section of the journal Frontiers in Endocrinology TWEAK and CD163 were determined. Children with obesity were re-evaluated after a Received: 31 March 2022 2-year intervention program consisting of diet and exercise. Weight loss was considered if Accepted: 07 June 2022 z-score Body Mass Index (BMI) decreased at least 0.5 Standard Deviations (SD). Published: 08 July 2022 Results: We observed higher CD163 levels in children with obesity compared to controls. Citation: Escartı´n R, Font M, No significant differences were observed in TWEAK and CD163/TWEAK ratio at baseline. González-Clemente JM, Vendrell J, After the 2-year intervention program, TWEAK levels were higher and CD163/TWEAK Caixàs A and Corripio R (2022) New Insights in Cytokines in Childhood ratio was lower in children with weight loss than those without weight loss. CD163 Obesity: Changes in TWEAK and decreased in both groups. CD163 After a 2-Year Intervention Program in Prepubertal Conclusion: TWEAK and CD163 seem to have a role in the pathogenesis of obesity in Children With Obesity. prepubertal children. Front. Endocrinol. 13:909201. doi: 10.3389/fendo.2022.909201 Keywords: TWEAK, CD163, childhood, obesity, prepubertal Frontiers in Endocrinology | www.frontiersin.org 1 July 2022 | Volume 13 | Article 909201 Escartı´n et al. TWEAK, CD163 in Childhood Obesity INTRODUCTION (BP). Written informed consent was obtained from all patients’ parents, and all investigations followed the Helsinki Declaration. The prevalence of childhood obesity has increased dramatically The study was approved by the Ethics Committee of our in recent decades, becoming a global public health problem (1). Institution (reference code 2004104). Pathological conditions associated with obesity, such as diabetes, hyperlipidemia, or hypertension (2), have been observed mainly Baseline Clinical Evaluation in adults. As the prevalence of childhood obesity increases, these Detailed medical, personal, and family history of obesity and conditions are becoming more common among infants and cardiometabolic risk was obtained from all subjects, including teenagers (3–8). birth weight and length for gestational age. A complete physical Obesity is associated with a chronic inflammatory state in examination was performed. Height was measured by a adipose tissue (9–11). In this context, we can observe altered Harpenden stadiometer to the nearest 0.1 cm and body levels of molecules involved in the regulation of inflammation, weight by balance scale to the nearest 0.1 kg. Waist called cytokines (12–14). circumference was measured with a tape at the middle point Research on cytokines has increased during the last years in between the last rib and the superior iliac crest, adjusted to the order to identify risk and protective factors of cardiovascular nearest 0.1 cm, and compared with an age and sex-reference disease and to generate potential target treatments (15, 16). population (29). All measurements were performed for Tumor Necrosis Factor Weak Inducer of Apoptosis duplication by the same investigator, with the patient in light (TWEAK), also known as Tumor Necrosis Factor (TNF) clothes and without shoes. The mean of the two determinations ligand superfamily member 12, is a cytokine involved in was used for calculations. Adiposity was evaluated by BMI multiple biological functions (12, 17, 18). It seems to play a (calculated as weight in kilograms divided by the square of protective role in the regulation of obesity and insulin resistance height in meters). Pubertal development was assessed by (15, 19, 20). It was observed that serum levels of soluble TWEAK direct physical examination according to Tanner staging. are lower in adults with severe obesity, and they increase in these Blood pressure was measured by triplicate with the Critikon patients after a significant weight loss (21). Dinamap 8100 automatic system (Johnson-Johnson Company, Cluster of Differentiation 163 (CD163) is a macrophage- Tampa, FL, USA), with an appropriate sized cuff and after at specific protein that increases in the context of inflammation least ten minutes resting in supine position. The lowest BP (22). In vitro, it has been identified as a scavenger receptor of value was recorded and evaluated using the percentiles of the TWEAK, promoting its degradation (23). Serum levels of International Task Force for Blood Pressure (30). CD163 are higher in obesity and insulin resistance, being a Obesity degree was fixed with z-BMI using the LMS method strong predictor of type 2 diabetes in adults (24). In (31). We also applied the obesity criteria by Cole (International cardiovascular diseases, a high CD163/TWEAK ratio was Obesity Task Force) (32) to our BMI data. found (25). Little is known about TWEAK and CD163 in children. The Baseline Metabolic Evaluation main objective of the study was to evaluate if a significant weight Blood samples were obtained after a 12-hours overnight fast. loss in children with obesity may induce changes in these Concentrations of soluble TWEAK, soluble CD163, alanine parameters after a 2-year lifestyle intervention program. In aminotransferase (ALT), uric acid, glucose, insulin, cholesterol addition, the investigation aimed to evaluate serum levels of and triglycerides were determined. Likewise, a standard 2-hours TWEAK, CD163, and CD163/TWEAK ratio in prepubertal oral glucose tolerance test was performed in subjects children with obesity compared to lean children. with obesity. Samples were stored at -80°C until their analysis. Plasma glucose was measured by the glucose hexokinase method, insulin PATIENTS AND METHODS by an electrochemiluminescent method, cholesterol and its fractions by cholesterol esterase/oxidase, and triglycerides by Seventy-three prepubertal children with obesity were included, lipase/glycerol kinase (Roche Diagnostics, Mannheim, from an outpatient long-term intervention program over a Germany). Intra- and inter-assay coefficient of variation (CV) period of 2 years. Inclusion criteria were the presence of values were 1.9–2.1% for glucose and 2.6–2.8% for obesity as defined by body mass index (BMI) > 2 standard insulin, respectively. deviation (SD) scores for age and sex upon Spanish normative Plasma soluble TWEAK was measured by an enzyme-linked charts (26), aged between 6 and 10 years and prepubertal immunoassay (ELISA) technique with a sensitivity of 0.02 pg/mL according to Tanner staging (27, 28). Controls were forty- (intra-assay CV <10%, inter-assay CV <9%). Plasma soluble seven prepubertal healthy children attending for preoperative CD163 was measured by ELISA with a sensitivity of 0.1 ng/mL blood tests before minor surgery. They were matched by age and (intra-assay CV <6%, inter-assay CV <7%). Impaired glucose gender. Exclusion criteria were the presence of endocrinopathies, metabolism was defined according to the American Diabetes obesity-associated syndrome, and any infectious or Association criteria (33). Insulin resistance was evaluated using inflammatory disease in the past 10 days, or taking medication the Homeostatic Model Assessment for Insulin Resistance ½HO ∗ fasting glucose ( μ mol=L) that affected weight, lipid metabolism, or arterial blood pressure MA IR = fasting insulin ( μ U=mL)22,5  (34). Frontiers in Endocrinology | www.frontiersin.org 2 July 2022 | Volume 13 | Article 909201 Escartı´n et al. TWEAK, CD163 in Childhood Obesity Intervention and Follow-Up CD163 or CD163/TWEAK ratio as dependent variables and After the baseline evaluation, 73 prepubertal children with age, sex, weight status (BMI), HOMA-IR and lipid profile, as obesity started a lifestyle intervention program that included a independent variables. A p value < 0.05 was considered significant. balanced norm caloric diet adjusted by age and a personally Analyses were performed with SAS v9.4, SAS Institute Inc., Cary, adapted exercise program. The diet contained 30% of energy NC, USA. intake from fat, 15% from protein, and 55% from carbohydrate (5% as sugar). A plan of 30–45 minutes of moderate exercise three times a week was negotiated. Television and video games RESULTS were limited to a maximum of 2 hours a day. Follow-up visits were scheduled every 4 months. 73 children with obesity and 47 controls were included in the After 2 years, a clinical and metabolic evaluation was study. Characteristics of subjects are shown in Table 1. performed with the same parameters as in the baseline Comparing cases and controls, CD163 levels were higher in evaluation. We considered a significant weight loss if the z- children with obesity. No statistically significant differences were score of BMI had decreased at least 0.5 SD (35). found in TWEAK and CD163/TWEAK ratio. After a 2-year follow-up of the cases, 62 completed the study Statistical Analysis and 11 dropped out (15%). 31 patients achieved a significant Data were expressed as mean ± SD for quantitative variables weight loss. Comparing patients with and without weight loss and as percentages for categorical variables. Logarithmic after the intervention program, TWEAK decreased in both transformation before the analysis was used when variables groups after the intervention program. However, we observed did not follow a normal distribution. Student’s t-test or that this parameter was higher in patients who achieved weight Mann-Whitney U test were used for comparing differences loss, before and after the intervention program. Serum levels of between groups. Paired t-test or Wilcoxon test was used to CD163 decreased after 2 years in both groups, and the decrease compare variables before and after the intervention program. was more pronounced in patients with weight loss (Figure 1). Bivariate correlations were evaluated with Pearson’s and CD163/TWEAK ratio was higher in children without weight Spearman’s coefficients as appropriate. Furthermore, some loss, and it increased after 2 years in this group (Figure 2). Data multivariate linear regression models were used. TWEAK, are shown in Table 2. TABLE 1 | Baseline Subjects Characteristics. With obesity (n = 73) Control (n = 47) p Sex 37 girls/36 boys 16 girls/31 boys 0.073 Age (years) 8.03 ± 1.08 7.74 ± 1.35 0.22 BMI (Kg/m2) 26.5 ± 3.07 16.2 ± 1.41 <0.001 z-BMI (SD) 4.76 ± 1.67 -0.27 ± 0.74 <0.001 Birth Weight (gr) 3337 ± 599.5 3194 ± 539.9 0.28 Birth Length (cm) 50.0 ± 2.61 50.1 ± 1.60 0.3 Familiar diabetes 2 35 (47%) 11 (23%) 0.01 Father BMI (Kg/m2) 28.6 ± 3.93 25.2 ± 2.31 0.003 Mother BMI (Kg/m2) 29.1 ± 7.83 23.1 ± 3.22 0.001 Acanthosis 23 (31%) 0 (0%) <0.001 Waist (cm) 81.3 ± 8.5 57.5 ± 6.05 0.035 SBP (mmHg) 109.2 ± 14.5 104.1 ± 9.60 0.026 DBP (mmHg) 63.4 ± 8.32 64.1 ± 9.25 0.672 Glucose (mg/dL) 83.7 ± 7.78 83.3 ± 5.04 0.804 Insulin (mU/mL)a 10 (5-15) 4 (2-5) <0.001 HOMA-IRa 1.97 (1.02-3.14) 0.80 (0.40-1.08) <0.001 Cholesterol (mg/dL) 155.5 ± 27.9 157.8 ± 31.4 0.621 Triglycerides(mg/dL)a 69 (52.5-87.5) 48 (40-54) <0.001 LDLc (mg/dL) 93.5 ± 24.1 82.6 ± 24.7 0.032 HDLc (mg/dL) 51.3 ± 12.8 65.5 ± 14.7 <0.001 Uric acid (mg/dL) 4.12 ± 0.85 3.41 ± 0.626 <0.001 ALT (U/L) 20.1 ± 6.68 19.2 ± 6.97 0.479 TWEAK (pg/mL) 1479.1 ± 1347.7 1184.9 ± 771.8 0.244 CD163 (ng/mL) 210.2 ± 48.9 187.2 ± 31.6 0.012 CD163/TWEAK ratio 0.14 ± 0,07 0.15 ± 0,10 0.255 Data are presented as mean ± SD or percentages. ALT, alaninetransferase; BMI, body mass index;CD163, Cluster of differentiation 163; DBP, diastolic blood pressure; HDLc, high density lipoprotein cholesterol; HOMA-IR, homeostatic model insulin resistance index; LDLc, low density lipoprotein cholesterol; SBP, systolic blood pressure; TWEAK, Tumor Necrosis Factor weak inducer of apoptosis. a Median (interquartile range). Frontiers in Endocrinology | www.frontiersin.org 3 July 2022 | Volume 13 | Article 909201 Escartı´n et al. TWEAK, CD163 in Childhood Obesity FIGURE 1 | CD163 decreased after 2 years in both groups, and the decrease was more pronounced in patients with weight loss. FIGURE 2 | CD163/TWEAK ratio was higher in children without weight loss, and it increased after 2 years in this group. To further understand the relationship between TWEAK and DISCUSSION CD163 and the rest of the variables, we carried out some bivariate correlation analysis with each of them. Age, sex, TWEAK and CD163 have been linked to obesity and associated HOMA, and lipid profile were included as independent cardiovascular diseases in adults (15). However, there are still few variables. No significant correlation among all these variables data about these cytokines in children. was found. Our investigation did not find statistically significant Forty-nine percent of the patients began puberty (assessed by differences in TWEAK or CD163/TWEAK ratio of children Tanner stage) during the follow-up phase. After adjusting the with obesity compared to controls. A possible explanation for regression model by Tanner, results were not modified. this might be that this cytokine is involved in processes such as Frontiers in Endocrinology | www.frontiersin.org 4 July 2022 | Volume 13 | Article 909201 Escartı´n et al. TWEAK, CD163 in Childhood Obesity TABLE 2 | Baseline and after 2-years follow up characteristics according to weight loss in children with obesity. Without weight loss (n = 31) With weight loss (n = 31) Sex 16 girls/15 boys 16 girls/15 boys Baseline Two years Baseline Two years pa Age (years) 7.6 ± 1.0 9.9 ± 1.1 d 8.4 ± 1.0c 10.4 ± 1.1 d BMI (Kg/m2) 26.0 ± 2.7 28.8 ± 3.4 d 26.5 ± 2.8 25.9 ± 3.3 d <0.001 z-BMI(SD) 4.68 ± 1.63 5.0 ± 1.7 d 4.6 ± 1.3 3.3 ± 1.3 d <0.001 Waist (cm) 78.4 ± 7.1 87.5 ± 10.6d 81.5 ± 6.4 c 83.6 ± 8.2 0.002 SBP (mmHg) 111.8 ± 16.1 111 ± 8.8 107 ± 12.4 108 ± 11.4 0.773 DBP (mmHg) 64.1 ± 8.6 69.5 ± 9.6 61.9 ± 8.8 61.7 ± 9.1 0.252 Glucose (mg/dL) 83.9 ± 6.7 88.5 ± 7.2d 84.2 ± 7.57 88.4 ± 8.87 d 0.829 Glucose 120min 110 ± 21.5 112 ± 16.7 112 ± 16.7 110 ± 14.9 0.394 Insulin (mU/mL)b 9 (5-13.2) 15 (10-20.2) d 10 (5-13) 11 (8-14) 0.374 HOMAb 1.9 (1.0-2.7) 3.3 (2.0-4.6) d 1.9 (0.9-2.7) 2.5 (1.8-3.1) d 0.371 Cholesterol (mg/dL) 155 ± 32.1 160 ± 30.1 157 ± 25.5 161 ± 28.1 0.907 b Triglycerides (mg/dL) 62 (53-76) 77 (61-89) d 72 (44-15) 75 (58-108) 0.437 LDLc (mg/dL) 92.1 ± 29.1 92.2 ± 28.6 95.8 ± 19.6 94.8 ± 20.3 0.685 HDLc (mg/dL) 55.1 ± 12.4 53.2 ± 12.9 49.8 ± 13.5 50.7 ± 15.2 0.506 Uric acid (mg/dL) 4.26 ± 0.80 4.68 ± 0.87 d 3.83 ± 0.82 c 4.12 ± 0.75 0.932 TWEAK (pg/mL) 1081.5 ± 699.6 1017.7 ± 720.7 1792.3 ± 1637.0 1535.9 ± 1370.4 0.032 CD163 (ng/mL) 215.0 ± 61.36 208.3 ± 49.2 206.2 ± 36.1 193.4 ± 34.1 0.334 CD163/TWEAK ratio 0.252 ± 0.148 0.289 ± 0.187 0.197 ± 0.120 0.198 ± 0.115 0.032 Data are presented as mean ± SD. a Mean of % of change between both groups. % of change= (end value - initial value)/initial value x 100. b Median (interquartile range). c Baseline comparison between those with and without weight loss (independent t-test) (p<0.05). d Two year paired t-test (p<0.05). BMI, body mass index; CD163, Cluster of differentiation 163; DBP, diastolic blood pressure; HDLc, high density lipoprotein cholesterol; HOMA-IR, homeostatic model insulin resistance index; LDLc, low density lipoprotein cholesterol; SBP, systolic blood pressure; TWEAK, Tumor Necrosis Factor Weak Inducer of Apoptosis. cell proliferation and differentiation (36), present in childhood This research has some limitations. It has a weak external growth. The protective role of TWEAK in obesity is not validity because all subjects were only from one center. However, demonstrated in prepubertal children, although some studies inclusion criteria for subjects are enough to guarantee a strong observed an anti-inflammatory role of this cytokine in obese internal validity in our results. Unfortunately we don’t have adults (25, 37). estradiol, testosterone levels or TWEAK evolution of control Regarding CD163, this cytokine is higher in adults with group after two years of follow-up. obesity, and known as a biomarker of insulin resistance (23). Our findings show that TWEAK and CD163 may be involved Carolan et al. observed elevated CD163 in children with in the pathogenesis of obesity in prepubertal children. Childhood obesity, suggesting that it could be a biomarker to prioritize is a necessary stage for the prevention of consequences derived lifestyle intervention in childhood (38). In our study, CD163 from obesity. This study opens an interesting line of research serum levels were also higher in children with obesity aimed at this objective. compared to lean. The present study is the first to observe a favorable effect of a 2-year lifestyle intervention program in prepubertal children DATA AVAILABILITY STATEMENT who achieved a significant weight loss compared with those who did not. We observed expected higher levels of TWEAK, The original contributions presented in the study are included in lower CD163/TWEAK ratio, and a more pronounced decrease of the article/supplementary material. Further inquiries can be CD163 in the group of patients who achieved weight loss. directed to the corresponding author. This study is the first one to observe the evolution of these parameters in prepubertal children, supporting the hypotheses that these cytokines may play a role in childhood obesity. One ETHICS STATEMENT study found similar results in adults with severe obesity after weight loss achieved by bariatric surgery (25). Kazankov et al. The studies involving human participants were reviewed and observed a decrease in CD163 after 10 weeks of a lifestyle a p p r o v e d b y C E I C f r o m F U N D A C I Ó I N S T I T U T intervention in children with a mean age of 12 years (39). D’INVESTIGACIÓ I INNOVACIÓ PARC TAULÍ (I3PT). Frontiers in Endocrinology | www.frontiersin.org 5 July 2022 | Volume 13 | Article 909201 Escartı´n et al. TWEAK, CD163 in Childhood Obesity Written informed consent to participate in this study was FUNDING provided by the participants’ legal guardian/next of kin. This project was supported by a grant from Fundació Parc Taulı́ 2004104. AUTHOR CONTRIBUTIONS AC, RC, and JG-C conceived the study. RC obtained informed consent and clinical variables. JV analyzed samples. MF and RE performed literature search. All authors were involved in writing ACKNOWLEDGMENTS the paper and had final approval of the submitted and published versions. We thank John Giba for his assistance in language editing. 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