Adipokine Profiles and Their Association with Body Composition and Disease Activity in Pediatric Crohn's Disease 

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In this study, we aimed to explore the association between body composition, adipocytokine profiles and disease activity in pediatric CD patients. Methods We recruited patients with active and quiescent CD, aged 6-18, along with age matched healthy controls. Body composition was analyzed via bio-impedance analysis, adipocytokines were assessed by ELISA–multiplex. Results Patients with active CD exhibited significantly elevated levels of adiponectin and resisitn compared to healthy controls and patients in remission even upon adjustment for body composition indices. Leptin correlated only with body composition and not with disease activity. Patients with active CD had relatively higher percentage of body fat and total body fat than the other groups. Conclusions This study underscores the complex interactions between adipocytokine profiles and disease activity in CD. Further studies are needed to investigate the potential mechanistic role of adiponectin and resisitin in CD pathogenesis. adiponectin resistin Crohn's disease pediatric Figures Figure 1 What is already known? Resistin, adiponectin and leptin have a role in inflammtory process and are secreted from adipose tissue. Resistin serum levels are increased in active adult CD as compared to adult patients in remission and healthy controls. What is new? Resistin and adiponectin serum levels are increased in children with active CD as compared to patients in clinical and biochemical remission. Resistin serum levels are independent of body composition indices. Leptin serum levels correlate with body fat content and not with inflammation. Introduction Creeping fat has long been associated as a radiological sign for Crohn’s disease. Accumulating data suggest that there is a substantial mechanistic role of intra-abdominal fat in the development and progression of IBD ( 1 , 2 ). It has been shown that patients with Crohn's disease (CD) have higher proportion of visceral fat compared to healthy subjects ( 2 ). Notably, active CD is associated with the presence of macrophage infiltrated ( 3 ) "creeping fat" - hyperplasia of the fat surrounding the intestine ( 4 ) which is a specific element of the intra-abdominal fat depot. Whether “creeping fat” is quantitatively a substantial component of intra-abdominal fat and if it is an active endocrine tissue secreting a unique adipocytokine hormonal profile is unknown. There is evidence that visceral fat functions as a major endocrine organ producing adipokines such adiponectin, leptin and resistin ( 1 )( 5 ) as well as a source of inflammatory cytokines such as IL-1, IL-6, IL-8, INFγ, TNF – α. ( 6 ). Although an association between adipokine levels and intestinal inflammation in patients with IBD has been demonstrated, controversy persists regarding their mechanistic role in disease process. Data comparing adult patients with CD to their healthy counterparts demonstrates a specific adipocytokine profile ( 7 ). Thus, the relation of intra-abdominal fat in general and the "creeping" fat surrounding involved segments of the gastrointestinal tract, in particular, and CD activity and clinical course is still unknown. Specifically, there is lack of data regarding intra-abdominal fat deposition and the adipocytokine profile in pediatric patients with CD in various degrees of activity. The primary aim of this study was to investigate the relation of body composition, the adipocytokine profile and disease activity in pediatric patients with CD with various degrees of disease activity. We postulated that patients with more active CD will have a higher pro inflammatory adipocytokine profile compared to patients in remission and healthy controls. Methods The study has been approved by the Rambam medical center IRB. Subjets with active CD and those with quiescent CD for at least 4 months in patients aged 6–18 years were recruited from the patients followed at the pediatric gastroenterology institute, Rambam medical center between 11/2021–6/2023. Disease activity was defined as wPCDAI ≥ 12.5 and was confirmed by endoscopy. Patients with active disease were recruited at diagnosis, before receiving any treatment. Quiescent disease was defined as wPCDAI > 12.5 along with normal levels of fecal calprotectin, CRP and ESR ( 8 ). Age matched healthy controls were recruited after exclusion of gastroenterological disease (normal biochemical and endoscopic evaluation) or healthy siblings of CD patients. In addition, normal healthy children performing growth hormone stimulation studies due to idiopathic short stature without any other evident diseases were recruited as controls from the pediatric endocrinology institute, Rambam medical center. Height was measured using a standard stadiometer. Body composition was evaluated using bio-impedance measurement at time of blood sampling (Tanita Body Analyzer). Bio-impedance is a method that involves no radiation, very simple and is considered accurate for visceral fat evaluation compared to CT ( 8 , 9 ). The visceral fat (VF) scale gives a score defined as healthy, at low risk or at high risk for metabolic derangement. Blood was drawn from all participants after an overnight fast and was centrifuged for 15 minutes at 4000 rpm. The serum was stored at -20 0 C for further evaluation of adipokines and cytokines. CRP, ESR, hemoglobin, albumin and fecal calprotectin were drawn separately in proximity of 2–5 days to the Bio-impedance analysis. Biochemical analyses Adipocytokines were measured using the ELISA multiplex protocol (Merck inc, kits (HADK1MAG-61K-02 for the analysis of adiponectin and resistin and HADK2MAG-61K-03 for the analysis of TNF α and leptin). CRP, ESR, hemoglobin, albumin and fecal calprotectin were drawn separately in proximity of 2–5 days to the Bio-impedance analysis. Statistical analysis Data is presented as means ± standard deviations. Parameters that were none normally distributed were natural log transformed for the sake of the analysis. Group comparisons were tested using analysis of variance. Post hoc comparisons were performed using the Bonferroni correction. Simple correlations were tested using the Pearson correlation coefficient. We used linear regression models to test predictors of the concentrations of adipocyokines of interest. The analysis was performed using SPSS V28. Results Study participants (table 1) Twenty-one healthy controls, 20 patients with active CD and 20 patients with CD in clinical remission participated in the study. The vast majority of both active and the remission groups had B1 phenotype (65% and 70%, respectively). Age was slightly lower in the control group, however, was comparable between the active and remission CD groups. Age at diagnosis, gender and Tanner stage were similar between the active and remission CD groups as were the location of the disease within the gastrointestinal tract and the disease behavior. BMI Z-score was significantly different between the groups (p = 0.006). Specifically, BMI Z-score was significantly lower in the active group compared the remission group (p = 0.005) while the patients in remission and the controls had a comparable BMI z score. Visceral fat categories were comparable between the groups as were lean body mass and fat mass. Importantly, upon adjustment of the visceral fat category to percent body fat, patients in remission had slightly greater adjusted visceral fat than their counterparts (p = 0.03). Biochemical analyses (table 2) Leptin levels were lower in the active disease group as compared to both patients in remission and healthy controls (p = 0.05 for both) (Fig. 1A), despite having comparable percent body fat. Adiponectin levels were significantly higher in the active disease group compared to the remission group (p-value = 0.003) and comparable between the control group and those in remission (Fig. 1C). Resistin levels were significantly higher in the active disease group compared to both control and remission groups (p-value < 0.001 for both) (Fig. 1E). CRP level was significantly higher in the active group compared to the quiescent group, as expected (p-value = 0.002). ESR and fecal calprotectin were significantly higher in the active group as compared to the remission group, while albumin and hemoglobin levels were lower, as expected (p < 0.001). TNF α serum levels were higher in the active group as compared to those in remission (p = 0.04). Relation of adipocytokine concentrations, body composition and BMI (table 3) Leptin was significantly correlated to all indices of body composition with highly significant r values. Adiponectin was only negatively associated with the BMI z score and with fat mass but not with percent body fat. Resistin had no significant association with any index of body composition tested. Performance of partial correlations while adjusting for sex and age resulted in very similar results for leptin and resistin while adiponectin was now not significantly associated with all body composition parameters. Relation of disease activity and adipocytokine concentrations We used linear regression models to test potential predictors of adipocytokine concentrations. The adipocytokine of interest was used as the dependent variable while independent variables included study group, age, sex and percent body fat (or alternatively – BMI z-score). Leptin was not associated with disease activity in this model (Fig. 1B). Leptin was significantly associated with percent body fat (p < 0.001). Using BMI z-score in this model instead of percent body fat yielded similar results showing no relation with disease activity. Adiponectin was significantly associated with disease activity in this model as those with active disease had significantly higher adiponectin levels compared to those in remission (p = 0.03) (Fig. 1D). Percent body fat or BMI z-score were not associated with adiponectin in these regressions. Resistin was also significantly associated with disease activity in this model as those with active disease had significantly higher resistin levels compared to those in remission and the control group (p < 0.001 for both) (Fig. 1F). Resistin was also significantly associated with age (p = 0.01) but not with BMI z-score or percent body fat. TNF-α levels were not significantly affected by disease activity in these models using BMI z-score or percent body fat as independent parameters. Similarly, IL-6 levels were comparable amongst the three groups in these models. Discussion We report adipokine serum concentrations in pediatric patients with varying degrees of disease activity. Our data clearly highlights two main findings: first, resistin levels are not associated in any way with body composition and are significantly increased in patients with active CD compared with their counterparts in remission and healthy controls. Secondly, adiponectin concentrations are increased in patients with active CD in comparison to those in remission regardless of different body composition indices. In contrast, “classic” inflammation markers such as TNF-α or IL-6 were not associated with disease activity in this analysis. Intra-abdominal fat is an active endocrine organ and its proportional relation to other body fat depots is a determinant of the adipocyte derived hormonal milieu ( 11 ). While these observations were mostly collected in healthy children or those with obesity, the mechanistic involvement of adipocyte-derived hormones in conditions such as inflammatory bowel disease is less clear. Previous data collected in adults has shown that mesenteric fat correlates with disease activity and severity in patients with active CD as compared to patients in remission ( 2 , 12 ) and can predict disease complications ( 12 , 13 ). The same observation was found also in the pediatric patients with active CD compared to healthy controls ( 15 ). Our study adds an additional insight into these relations as we show the typical adipococytokine profile that is associated with active CD, independent of body composition indices. Specifically, adiponectin and resisitin were tightly linked to disease activity and not to anthropometric indices. As patients with active disease were leaner than those in remission, with no significant differences in mean visceral fat categories, body fat mass or percent body fat between these groups, one can speculate that a specific adipocyte depot (“creeping fat”?) may be responsible for these adipocytokine disparities. Adiponectin is an adipocytokine that is negatively correlated with total body fat, has anti-inflammatory actions and serves as an insulin sensitizer by inducing fatty acid oxidation in the liver ( 16 ). In addition, adiponectin serves as a critical modulator of innate and adaptive immunity in various metabolic diseases ( 17 ). In the context of IBD, hypertrophied mesenteric fat resected from patients with CD was found to produce more adiponectin than non-hypertrophied tissue ( 18 ), yet the role of adiponectin (ADN) in the inflammatory process is not clear. While in humans adiponectin has an anti-inflammatory effect ( 7 ), animal colitis models and in vitro studies found contradictory findings ( 7 ). Adiponectin receptors, expressed on monocytes, B-lymphocytes and NK cells ( 19 ), promote its anti-inflammatory function through suppression of NF ϏB and stimulation of secretion of anti-inflammatory cytokines, such as IL-10 and IL-1 receptor antagonist ( 19 ). Nevertheless, there is inconsistency in the data regarding adiponectin serum levels and its expression in mesenteric fat in relation to disease activity ( 18 , 20 – 22 ). A recent meta-analysis ( 23 ) demonstrated that adiponectin concentrations do not differ between healthy individuals and those with CD, yet this analysis did not differentiate between patients by disease activity or by other significant determinants of adiponectin concentration (sex and percent body fat). We observed that higher adiponectin concentrations are associated with disease activity in our study population, even after adjustment for other determinants of adiponection concentration. This finding raises the question whether the source of adiponectin in this case is the “creeping fat” which may secrete anti-inflammatory cytokines in order to modulate the local inflammatory process. Resistin as an adipocytokine is involved in inflammatory as well as proliferative processes ( 24 ). Resistin levels have been shown to be higher in patients with IBD in comparison to healthy controls ( 22 , 25 ). Of note – patients with active CD have higher resistin levels than those in remission ( 26 ). Our findings strengthen these observations further by showing that resistin concentration are higher in active CD even after adjustments for body composition and sex. This observation is in line with a previous small pediatric cohort that investigated several serum proteins in 76 plasma samples, however no data regarding disease activity was provided ( 27 ). Elevated resistin levels were also found in pediatric patients that needed biologic treatment as compared to those who did not, which may imply a correlation with disease severity ( 28 ). Resistin is expressed in human macrophages, mononuclear lymphocytes, neutrophils and adipose tissue and is over expressed in response to pro-inflammatory cytokines, such as IL-6, TNF α and bacterial lipopolisaccharides (LPS) ( 29 , 30 ). Resistin is considered a pro-inflammatory cytokine. Nevertheless, animal studies have demonstrated an anti- bacterial properties by stimulation of the innate immune response ( 30 ). Moreover, it exhibits immunomodulatory function by diminishing the pro inflammatory effects of LPS through interaction with LPS receptor Toll-like receptor 4 (TLR4) and by modulation of downstream signaling. Additionally, it modulates STAT3 and TBK1 signaling, favoring a transition from pro-inflammatory to anti-inflammatory responses ( 31 ). Elevated resistin concentrations in active CD may thus be a biomarker of active inflammation of surrounding adipose tissue involved gut segments or perhaps an active local anti-inflammatory response. Whether the source of resistin is from immune cells within the “creeping fat” or from other adipose tissue elements remains to be determined. Our findings show similar serum concentrations of IL-6 and TNF α in subjects with and without CD and no relation of these cytokines to disease activity or body composition. A similar observation was demonstrated by Avdagic et al ( 32 ). As it is well established that these cytokines are active local players in the inflammatory process in IBD in general and in CD in particular, it is reasonable to assume that there is a discrepancy between systemic and local concentrations of these pro-inflammatory cytokines. In other words, concentrations of these cytokines are probably greater in sites of active inflammation and disease activity yet the systemic concentrations are much lower and thus this difference is difficult to detect using blood samples. Our study has several limitations. Firstly, visceral fat was not measured using the gold standard technique –but with a body analyzer, which has been demonstrated to be accurate as CT in the estimation of VF ( 9 , 10 ). Another limitation of this study is the relatively small sample size. The rather modest sample size prevented us from conducting subgroup analyses based on disease severity, phenotype or treatment within the remission group. However, even with this relatively modest sample, significant relevant differences in specific adipocytokines emerged, suggesting that the findings may be valid. In conclusion, this study highlights a unique adipocytokine profile in pediatric patients with CD consisting of elevated resistin and adiponectin concentrations independent of potential confoundres. Whether adiponectin and resistin are merely biomarkers or active participants in the disease process is a topic for further investigations. Elucidating and establishing a mechanistic role of adipocytokines in CD development may lead to the discovery of novel pharmacological approaches and drug targets to improve the treatment of patients with CD. Declarations Ethics statement: Participant's guardians signed an informed consent form at recruitment. We show for the first time a significant association between disease activity and resistin and adiponectin, independent of body composition indices. Funding: This study was funded by grant from the Israeli Association for Pediatric Gastroenterology and Hepatology No conflict of interest for all authors Competing interest declaration No conflict of interest for all authors Contributions RMR- conceptualisation, patient recruitment and evaluation, writing – original draft, investigation, methodology. MC - patient recruitment, writing– review, editing. IR - patient recruitment, writing – review, editing. JG - patient recruitment, writing– review, editing. ISC - patient recruitment, writing– review, editing. RW - supervision, conceptualization, writing– review& - editing, formal analysis, methodology. RS - supervision, conceptualization, writing– review & editing, investigation, methodology. The data provided by the authors is not part of a repository or public database. The PI (RMR) will be happy to discuss sharing the data with interested researchers upon request. References Fink C, Karagiannides I, Bakirtzi K, Pothoulakis C. 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Available from: https://doi.org/10.1016/j.immuni.2019.03.017 Li Y, Yang Q, Cai D, Guo H, Fang J, Cui H, et al. Resistin, a Novel Host Defense Peptide of Innate Immunity. Front Immunol. 2021;12(June):1–14. Choe JY, Choi S, Song KH, Jang HJ, Choi KH, Yi DY, et al. Incidence and Prevalence Trends of Pediatric Inflammatory Bowel Disease in the Daegu-Kyungpook Province From 2017 to 2020. Front Pediatr. 2022;9(January):1–7. Nesina Avdagić 1, Nermina Babić, Mensura Šeremet, Marina Delić-Šarac, Zahida Drače, Amir Denjalić EN-I. Tumor necrosis factor-alpha serum level in assessment of disease activity in inflammatory bowel diseases. Med Glas. 2013;10(2):211–6. Tables Tables 1 to 3 are available in the Supplementary Files section Additional Declarations No competing interests reported. Supplementary Files Table12.pdf Table2.pdf Table3.pdf Cite Share Download PDF Status: Published Journal Publication published 29 Apr, 2025 Read the published version in Digestive Diseases and Sciences → Version 1 posted Editorial decision: Revision requested 07 Jan, 2025 Reviews received at journal 28 Dec, 2024 Reviewers agreed at journal 11 Dec, 2024 Reviewers invited by journal 19 Nov, 2024 Editor assigned by journal 18 Nov, 2024 Submission checks completed at journal 18 Nov, 2024 First submitted to journal 13 Nov, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5444107","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":380278785,"identity":"60958076-fbcf-4555-b5e1-9ecd5c83ed12","order_by":0,"name":"Ramit 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Rosen","email":"","orcid":"","institution":"Rambam Health Care Campus","correspondingAuthor":false,"prefix":"","firstName":"Irit","middleName":"","lastName":"Rosen","suffix":""},{"id":380278792,"identity":"886a642c-0fbe-4b6a-a2c6-455d3ecca444","order_by":3,"name":"Inna Spector-Cohen","email":"","orcid":"","institution":"Rambam Health Care Campus","correspondingAuthor":false,"prefix":"","firstName":"Inna","middleName":"","lastName":"Spector-Cohen","suffix":""},{"id":380278795,"identity":"9af991a6-e4ab-4258-8039-7aa99778bca3","order_by":4,"name":"Jamal Garah","email":"","orcid":"","institution":"Rambam Health Care Campus","correspondingAuthor":false,"prefix":"","firstName":"Jamal","middleName":"","lastName":"Garah","suffix":""},{"id":380278796,"identity":"971b7c9a-622c-4742-bf13-aab737d2dda5","order_by":5,"name":"Ram Weiss","email":"","orcid":"","institution":"Rambam Health Care Campus","correspondingAuthor":false,"prefix":"","firstName":"Ram","middleName":"","lastName":"Weiss","suffix":""},{"id":380278798,"identity":"a6cd0c59-062a-42d3-9695-7b4b994913b6","order_by":6,"name":"Ron Shaoul","email":"","orcid":"","institution":"Rambam Health Care Campus","correspondingAuthor":false,"prefix":"","firstName":"Ron","middleName":"","lastName":"Shaoul","suffix":""}],"badges":[],"createdAt":"2024-11-13 06:08:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5444107/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5444107/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10620-025-08941-z","type":"published","date":"2025-04-29T15:57:21+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":72285131,"identity":"b4756406-a236-4d92-9ca3-97777bd9d99a","added_by":"auto","created_at":"2024-12-24 16:52:40","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":121665,"visible":true,"origin":"","legend":"\u003cp\u003eAdipocytokines levels adjusted to age, sex, % body fat and BMI Z-score\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-5444107/v1/1498528a1b5c7a69de68ade8.png"},{"id":81988045,"identity":"9cedd160-37f6-46ad-9455-a1d303680c02","added_by":"auto","created_at":"2025-05-05 16:07:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":637492,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5444107/v1/791a0e16-df0b-4cd9-ac6c-36a12964cba2.pdf"},{"id":72286237,"identity":"f381b330-a064-4c33-a12a-5375b249db4a","added_by":"auto","created_at":"2024-12-24 17:00:40","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":283185,"visible":true,"origin":"","legend":"","description":"","filename":"Table12.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5444107/v1/eb577c47f3ea7f7f65ef7785.pdf"},{"id":72285134,"identity":"53eeaa8b-84cd-4659-a78a-b68e4255cef9","added_by":"auto","created_at":"2024-12-24 16:52:40","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":349310,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5444107/v1/a9f3429d6bae9f4d2d14dac2.pdf"},{"id":72285132,"identity":"fcd35791-713c-46df-8e54-6471b0ebcffc","added_by":"auto","created_at":"2024-12-24 16:52:40","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":277559,"visible":true,"origin":"","legend":"","description":"","filename":"Table3.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5444107/v1/59d2a3d762c4d7e4644398be.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Adipokine Profiles and Their Association with Body Composition and Disease Activity in Pediatric Crohn's Disease ","fulltext":[{"header":"What is already known?","content":"\u003cul\u003e\n \u003cli\u003eResistin, adiponectin and leptin have a role in inflammtory process and are secreted from adipose tissue.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eResistin serum levels are increased in active adult CD as compared to adult patients in remission and healthy controls.\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eWhat is new?\u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eResistin and adiponectin serum levels are increased in children with active CD as compared to patients in clinical and biochemical remission.\u003c/li\u003e\n \u003cli\u003e\u0026nbsp;Resistin serum levels are independent of body composition indices.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eLeptin serum levels correlate with body fat content and not with inflammation. \u0026nbsp;\u0026nbsp;\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"Introduction","content":"\u003cp\u003eCreeping fat has long been associated as a radiological sign for Crohn\u0026rsquo;s disease. Accumulating data suggest that there is a substantial mechanistic role of intra-abdominal fat in the development and progression of IBD (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). It has been shown that patients with Crohn's disease (CD) have higher proportion of visceral fat compared to healthy subjects (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Notably, active CD is associated with the presence of macrophage infiltrated (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) \"creeping fat\" - hyperplasia of the fat surrounding the intestine (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) which is a specific element of the intra-abdominal fat depot. Whether \u0026ldquo;creeping fat\u0026rdquo; is quantitatively a substantial component of intra-abdominal fat and if it is an active endocrine tissue secreting a unique adipocytokine hormonal profile is unknown.\u003c/p\u003e \u003cp\u003eThere is evidence that visceral fat functions as a major endocrine organ producing adipokines such adiponectin, leptin and resistin (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e)(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) as well as a source of inflammatory cytokines such as IL-1, IL-6, IL-8, INFγ, TNF \u0026ndash; α. (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Although an association between adipokine levels and intestinal inflammation in patients with IBD has been demonstrated, controversy persists regarding their mechanistic role in disease process. Data comparing adult patients with CD to their healthy counterparts demonstrates a specific adipocytokine profile (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Thus, the relation of intra-abdominal fat in general and the \"creeping\" fat surrounding involved segments of the gastrointestinal tract, in particular, and CD activity and clinical course is still unknown. Specifically, there is lack of data regarding intra-abdominal fat deposition and the adipocytokine profile in pediatric patients with CD in various degrees of activity.\u003c/p\u003e \u003cp\u003eThe primary aim of this study was to investigate the relation of body composition, the adipocytokine profile and disease activity in pediatric patients with CD with various degrees of disease activity. We postulated that patients with more active CD will have a higher pro inflammatory adipocytokine profile compared to patients in remission and healthy controls.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e The study has been approved by the Rambam medical center IRB. Subjets with active CD and those with quiescent CD for at least 4 months in patients aged 6\u0026ndash;18 years were recruited from the patients followed at the pediatric gastroenterology institute, Rambam medical center between 11/2021\u0026ndash;6/2023. Disease activity was defined as wPCDAI\u0026thinsp;\u0026ge;\u0026thinsp;12.5 and was confirmed by endoscopy. Patients with active disease were recruited at diagnosis, before receiving any treatment. Quiescent disease was defined as wPCDAI\u0026thinsp;\u0026gt;\u0026thinsp;12.5 along with normal levels of fecal calprotectin, CRP and ESR (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Age matched healthy controls were recruited after exclusion of gastroenterological disease (normal biochemical and endoscopic evaluation) or healthy siblings of CD patients. In addition, normal healthy children performing growth hormone stimulation studies due to idiopathic short stature without any other evident diseases were recruited as controls from the pediatric endocrinology institute, Rambam medical center.\u003c/p\u003e \u003cp\u003eHeight was measured using a standard stadiometer. Body composition was evaluated using bio-impedance measurement at time of blood sampling (Tanita Body Analyzer). Bio-impedance is a method that involves no radiation, very simple and is considered accurate for visceral fat evaluation compared to CT (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). The visceral fat (VF) scale gives a score defined as healthy, at low risk or at high risk for metabolic derangement. Blood was drawn from all participants after an overnight fast and was centrifuged for 15 minutes at 4000 rpm. The serum was stored at -20\u003csup\u003e0\u003c/sup\u003eC for further evaluation of adipokines and cytokines. CRP, ESR, hemoglobin, albumin and fecal calprotectin were drawn separately in proximity of 2\u0026ndash;5 days to the Bio-impedance analysis.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eBiochemical analyses\u003c/h2\u003e \u003cp\u003eAdipocytokines were measured using the ELISA multiplex protocol (Merck inc, kits (HADK1MAG-61K-02 for the analysis of adiponectin and resistin and HADK2MAG-61K-03 for the analysis of TNF α and leptin). CRP, ESR, hemoglobin, albumin and fecal calprotectin were drawn separately in proximity of 2\u0026ndash;5 days to the Bio-impedance analysis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eData is presented as means\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviations. Parameters that were none normally distributed were natural log transformed for the sake of the analysis. Group comparisons were tested using analysis of variance. Post hoc comparisons were performed using the Bonferroni correction. Simple correlations were tested using the Pearson correlation coefficient. We used linear regression models to test predictors of the concentrations of adipocyokines of interest. The analysis was performed using SPSS V28.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStudy participants (table 1)\u003c/h2\u003e \u003cp\u003eTwenty-one healthy controls, 20 patients with active CD and 20 patients with CD in clinical remission participated in the study. The vast majority of both active and the remission groups had B1 phenotype (65% and 70%, respectively). Age was slightly lower in the control group, however, was comparable between the active and remission CD groups. Age at diagnosis, gender and Tanner stage were similar between the active and remission CD groups as were the location of the disease within the gastrointestinal tract and the disease behavior. BMI Z-score was significantly different between the groups (p\u0026thinsp;=\u0026thinsp;0.006). Specifically, BMI Z-score was significantly lower in the active group compared the remission group (p\u0026thinsp;=\u0026thinsp;0.005) while the patients in remission and the controls had a comparable BMI z score. Visceral fat categories were comparable between the groups as were lean body mass and fat mass. Importantly, upon adjustment of the visceral fat category to percent body fat, patients in remission had slightly greater adjusted visceral fat than their counterparts (p\u0026thinsp;=\u0026thinsp;0.03).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eBiochemical analyses (table 2)\u003c/h3\u003e\n\u003cp\u003eLeptin levels were lower in the active disease group as compared to both patients in remission and healthy controls (p\u0026thinsp;=\u0026thinsp;0.05 for both) (Fig.\u0026nbsp;1A), despite having comparable percent body fat. Adiponectin levels were significantly higher in the active disease group compared to the remission group (p-value\u0026thinsp;=\u0026thinsp;0.003) and comparable between the control group and those in remission (Fig.\u0026nbsp;1C). Resistin levels were significantly higher in the active disease group compared to both control and remission groups (p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for both) (Fig.\u0026nbsp;1E).\u003c/p\u003e \u003cp\u003eCRP level was significantly higher in the active group compared to the quiescent group, as expected (p-value\u0026thinsp;=\u0026thinsp;0.002). ESR and fecal calprotectin were significantly higher in the active group as compared to the remission group, while albumin and hemoglobin levels were lower, as expected (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). TNF α serum levels were higher in the active group as compared to those in remission (p\u0026thinsp;=\u0026thinsp;0.04).\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eRelation of adipocytokine concentrations, body composition and BMI (table 3)\u003c/h2\u003e \u003cp\u003eLeptin was significantly correlated to all indices of body composition with highly significant r values. Adiponectin was only negatively associated with the BMI z score and with fat mass but not with percent body fat. Resistin had no significant association with any index of body composition tested. Performance of partial correlations while adjusting for sex and age resulted in very similar results for leptin and resistin while adiponectin was now not significantly associated with all body composition parameters.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eRelation of disease activity and adipocytokine concentrations\u003c/h3\u003e\n\u003cp\u003eWe used linear regression models to test potential predictors of adipocytokine concentrations. The adipocytokine of interest was used as the dependent variable while independent variables included study group, age, sex and percent body fat (or alternatively \u0026ndash; BMI z-score).\u003c/p\u003e \u003cp\u003eLeptin was not associated with disease activity in this model (Fig.\u0026nbsp;1B). Leptin was significantly associated with percent body fat (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Using BMI z-score in this model instead of percent body fat yielded similar results showing no relation with disease activity.\u003c/p\u003e \u003cp\u003eAdiponectin was significantly associated with disease activity in this model as those with active disease had significantly higher adiponectin levels compared to those in remission (p\u0026thinsp;=\u0026thinsp;0.03) (Fig.\u0026nbsp;1D). Percent body fat or BMI z-score were not associated with adiponectin in these regressions.\u003c/p\u003e \u003cp\u003eResistin was also significantly associated with disease activity in this model as those with active disease had significantly higher resistin levels compared to those in remission and the control group (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 for both) (Fig.\u0026nbsp;1F). Resistin was also significantly associated with age (p\u0026thinsp;=\u0026thinsp;0.01) but not with BMI z-score or percent body fat.\u003c/p\u003e \u003cp\u003eTNF-α levels were not significantly affected by disease activity in these models using BMI z-score or percent body fat as independent parameters. Similarly, IL-6 levels were comparable amongst the three groups in these models.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe report adipokine serum concentrations in pediatric patients with varying degrees of disease activity. Our data clearly highlights two main findings: first, resistin levels are not associated in any way with body composition and are significantly increased in patients with active CD compared with their counterparts in remission and healthy controls. Secondly, adiponectin concentrations are increased in patients with active CD in comparison to those in remission regardless of different body composition indices. In contrast, \u0026ldquo;classic\u0026rdquo; inflammation markers such as TNF-\u0026alpha; or IL-6 were not associated with disease activity in this analysis.\u003c/p\u003e\n\u003cp\u003eIntra-abdominal fat is an active endocrine organ and its proportional relation to other body fat depots is a determinant of the adipocyte derived hormonal milieu (\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e). While these observations were mostly collected in healthy children or those with obesity, the mechanistic involvement of adipocyte-derived hormones in conditions such as inflammatory bowel disease is less clear. Previous data collected in adults has shown that mesenteric fat correlates with disease activity and severity in patients with active CD as compared to patients in remission (\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e) and can predict disease complications (\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e13\u003c/span\u003e). The same observation was found also in the pediatric patients with active CD compared to healthy controls (\u003cspan class=\"CitationRef\"\u003e15\u003c/span\u003e). Our study adds an additional insight into these relations as we show the typical adipococytokine profile that is associated with active CD, independent of body composition indices. Specifically, adiponectin and resisitin were tightly linked to disease activity and not to anthropometric indices. As patients with active disease were leaner than those in remission, with no significant differences in mean visceral fat categories, body fat mass or percent body fat between these groups, one can speculate that a specific adipocyte depot (\u0026ldquo;creeping fat\u0026rdquo;?) may be responsible for these adipocytokine disparities.\u003c/p\u003e\n\u003cp\u003eAdiponectin is an adipocytokine that is negatively correlated with total body fat, has anti-inflammatory actions and serves as an insulin sensitizer by inducing fatty acid oxidation in the liver (\u003cspan class=\"CitationRef\"\u003e16\u003c/span\u003e). In addition, adiponectin serves as a critical modulator of innate and adaptive immunity in various metabolic diseases (\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e). In the context of IBD, hypertrophied mesenteric fat resected from patients with CD was found to produce more adiponectin than non-hypertrophied tissue (\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e), yet the role of adiponectin (ADN) in the inflammatory process is not clear. While in humans adiponectin has an anti-inflammatory effect (\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e), animal colitis models and in vitro studies found contradictory findings (\u003cspan class=\"CitationRef\"\u003e7\u003c/span\u003e). Adiponectin receptors, expressed on monocytes, B-lymphocytes and NK cells (\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e), promote its anti-inflammatory function through suppression of NF ϏB and stimulation of secretion of anti-inflammatory cytokines, such as IL-10 and IL-1 receptor antagonist (\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e). Nevertheless, there is inconsistency in the data regarding adiponectin serum levels and its expression in mesenteric fat in relation to disease activity (\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e). A recent meta-analysis (\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e) demonstrated that adiponectin concentrations do not differ between healthy individuals and those with CD, yet this analysis did not differentiate between patients by disease activity or by other significant determinants of adiponectin concentration (sex and percent body fat). We observed that higher adiponectin concentrations are associated with disease activity in our study population, even after adjustment for other determinants of adiponection concentration. This finding raises the question whether the source of adiponectin in this case is the \u0026ldquo;creeping fat\u0026rdquo; which may secrete anti-inflammatory cytokines in order to modulate the local inflammatory process.\u003c/p\u003e\n\u003cp\u003eResistin as an adipocytokine is involved in inflammatory as well as proliferative processes (\u003cspan class=\"CitationRef\"\u003e24\u003c/span\u003e). Resistin levels have been shown to be higher in patients with IBD in comparison to healthy controls (\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e). Of note \u0026ndash; patients with active CD have higher resistin levels than those in remission (\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e). Our findings strengthen these observations further by showing that resistin concentration are higher in active CD even after adjustments for body composition and sex. This observation is in line with a previous small pediatric cohort that investigated several serum proteins in 76 plasma samples, however no data regarding disease activity was provided (\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e). Elevated resistin levels were also found in pediatric patients that needed biologic treatment as compared to those who did not, which may imply a correlation with disease severity (\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e). Resistin is expressed in human macrophages, mononuclear lymphocytes, neutrophils and adipose tissue and is over expressed in response to pro-inflammatory cytokines, such as IL-6, TNF \u0026alpha; and bacterial lipopolisaccharides (LPS) (\u003cspan class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e). Resistin is considered a pro-inflammatory cytokine. Nevertheless, animal studies have demonstrated an anti- bacterial properties by stimulation of the innate immune response (\u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e). Moreover, it exhibits immunomodulatory function by diminishing the pro inflammatory effects of LPS through interaction with LPS receptor Toll-like receptor 4 (TLR4) and by modulation of downstream signaling. Additionally, it modulates STAT3 and TBK1 signaling, favoring a transition from pro-inflammatory to anti-inflammatory responses (\u003cspan class=\"CitationRef\"\u003e31\u003c/span\u003e). Elevated resistin concentrations in active CD may thus be a biomarker of active inflammation of surrounding adipose tissue involved gut segments or perhaps an active local anti-inflammatory response. Whether the source of resistin is from immune cells within the \u0026ldquo;creeping fat\u0026rdquo; or from other adipose tissue elements remains to be determined.\u003c/p\u003e\n\u003cp\u003eOur findings show similar serum concentrations of IL-6 and TNF \u0026alpha; in subjects with and without CD and no relation of these cytokines to disease activity or body composition. A similar observation was demonstrated by Avdagic et al (\u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e). As it is well established that these cytokines are active local players in the inflammatory process in IBD in general and in CD in particular, it is reasonable to assume that there is a discrepancy between systemic and local concentrations of these pro-inflammatory cytokines. In other words, concentrations of these cytokines are probably greater in sites of active inflammation and disease activity yet the systemic concentrations are much lower and thus this difference is difficult to detect using blood samples.\u003c/p\u003e\n\u003cp\u003eOur study has several limitations. Firstly, visceral fat was not measured using the gold standard technique \u0026ndash;but with a body analyzer, which has been demonstrated to be accurate as CT in the estimation of VF (\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e). Another limitation of this study is the relatively small sample size. The rather modest sample size prevented us from conducting subgroup analyses based on disease severity, phenotype or treatment within the remission group. However, even with this relatively modest sample, significant relevant differences in specific adipocytokines emerged, suggesting that the findings may be valid.\u003c/p\u003e\n\u003cp\u003eIn conclusion, this study highlights a unique adipocytokine profile in pediatric patients with CD consisting of elevated resistin and adiponectin concentrations independent of potential confoundres. Whether adiponectin and resistin are merely biomarkers or active participants in the disease process is a topic for further investigations. Elucidating and establishing a mechanistic role of adipocytokines in CD development may lead to the discovery of novel pharmacological approaches and drug targets to improve the treatment of patients with CD.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cu\u003eEthics statement:\u003c/u\u003e Participant's guardians signed an informed consent form at recruitment.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe show for the first time a significant association between disease activity and resistin and adiponectin, independent of body composition indices.\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eFunding:\u003c/u\u003e This study was funded by grant from the Israeli Association for Pediatric Gastroenterology and Hepatology\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNo conflict of interest for all authors\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eCompeting interest declaration\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eNo conflict of interest for all authors\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eContributions\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eRMR- conceptualisation, patient recruitment and evaluation, writing \u0026ndash; original draft, investigation, methodology.\u003c/p\u003e\n\u003cp\u003eMC - patient recruitment, writing\u0026ndash; review, editing.\u003c/p\u003e\n\u003cp\u003eIR - patient recruitment, writing \u0026ndash; review, editing.\u003c/p\u003e\n\u003cp\u003eJG - patient recruitment, writing\u0026ndash; review, editing.\u003c/p\u003e\n\u003cp\u003eISC - patient recruitment, writing\u0026ndash; review, editing.\u003c/p\u003e\n\u003cp\u003eRW - supervision, conceptualization, writing\u0026ndash; review\u0026amp;amp - editing, formal analysis, methodology.\u003c/p\u003e\n\u003cp\u003eRS - supervision, conceptualization, writing\u0026ndash; review \u0026amp;amp; editing, investigation, methodology.\u003c/p\u003e\n\u003cp\u003eThe data provided by the authors is not part of a repository or public database. The PI (RMR) will be happy to discuss sharing the data with interested researchers upon request.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eFink C, Karagiannides I, Bakirtzi K, Pothoulakis C. Adipose tissue and inflammatory bowel disease pathogenesis. Inflammatory Bowel Diseases. 2012.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDesreumaux P, Ernst O, Geboes K, Gambiez L, Berrebi D, Muller-Alouf H, et al. Inflammatory alterations in mesenteric adipose tissue in Crohn\u0026rsquo;s disease. Gastroenterology. 1999;\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLissner D, Schumann M, Batra A, Kredel LI, K\u0026uuml;hl AA, Erben U, et al. Monocyte and M1 macrophage-induced barrier defect contributes to chronic intestinal inflammation in IBD. Inflamm Bowel Dis. 2015;21(6):1297\u0026ndash;305.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWeidinger C, Hegazy AN, Siegmund B. 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Med Glas. 2013;10(2):211\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"digestive-diseases-and-sciences","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ddsj","sideBox":"Learn more about [Digestive Diseases and Sciences](http://link.springer.com/journal/10620)","snPcode":"10620","submissionUrl":"https://submission.nature.com/new-submission/10620/3","title":"Digestive Diseases and Sciences","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"adiponectin, resistin, Crohn's disease, pediatric","lastPublishedDoi":"10.21203/rs.3.rs-5444107/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5444107/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjectives\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEmerging evidence implicates an important role for visceral fat, particularly \"creeping fat\", in the pathogeneses and progression of inflammatory bowel diseases (IBD), specifically Crohn's disease (CD).\u003c/p\u003e\n\u003cp\u003eIn this study, we aimed to explore the association between body composition, adipocytokine profiles and disease activity in pediatric CD patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe recruited patients with active and quiescent CD, aged 6-18, along with age matched healthy controls. Body composition was analyzed via bio-impedance analysis, adipocytokines were assessed by ELISA–multiplex.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients with active CD exhibited significantly elevated levels of adiponectin and resisitn compared to healthy controls and patients in remission even upon adjustment for body composition indices. Leptin correlated only with body composition and not with disease activity. Patients with active CD had relatively higher percentage of body fat and total body fat than the other groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study underscores the complex interactions between adipocytokine profiles and disease activity in CD. Further studies are needed to investigate the potential mechanistic role of adiponectin and resisitin in CD pathogenesis.\u003c/p\u003e","manuscriptTitle":"Adipokine Profiles and Their Association with Body Composition and Disease Activity in Pediatric Crohn's Disease ","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-12-24 16:52:35","doi":"10.21203/rs.3.rs-5444107/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-01-07T17:46:10+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-12-28T14:59:29+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"196975762156310939909249753194247435047","date":"2024-12-11T21:37:09+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-11-20T04:48:18+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-11-18T21:12:40+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-11-18T14:51:14+00:00","index":"","fulltext":""},{"type":"submitted","content":"Digestive Diseases and Sciences","date":"2024-11-13T05:53:47+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"digestive-diseases-and-sciences","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ddsj","sideBox":"Learn more about [Digestive Diseases and Sciences](http://link.springer.com/journal/10620)","snPcode":"10620","submissionUrl":"https://submission.nature.com/new-submission/10620/3","title":"Digestive Diseases and Sciences","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"cb7d9943-1209-4c47-9d8c-e759cfef0e5b","owner":[],"postedDate":"December 24th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-05-05T16:05:00+00:00","versionOfRecord":{"articleIdentity":"rs-5444107","link":"https://doi.org/10.1007/s10620-025-08941-z","journal":{"identity":"digestive-diseases-and-sciences","isVorOnly":false,"title":"Digestive Diseases and Sciences"},"publishedOn":"2025-04-29 15:57:21","publishedOnDateReadable":"April 29th, 2025"},"versionCreatedAt":"2024-12-24 16:52:35","video":"","vorDoi":"10.1007/s10620-025-08941-z","vorDoiUrl":"https://doi.org/10.1007/s10620-025-08941-z","workflowStages":[]},"version":"v1","identity":"rs-5444107","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5444107","identity":"rs-5444107","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}