title: Upregulation of inflammasome activity and increased gut permeability are associated with obesity in children and adolescents.
abstract: Immune activation contributes to the persistent state of inflammation associated with metabolic dysfunction in obesity. The specific immune receptors that sense metabolic stress signals and trigger inflammation are nevertheless largely unknown, and little is known on inflammatory and immune gene regulation in obesity.
  
  
  
  The study includes a cross-sectional and a longitudinal arm. Forty children and adolescents were enrolled: 22 obese subjects and 18 age-matched normal weight controls. Obese subjects participated in an 18-month therapeutic protocol, based on intensive lifestyle modification (dietary regimen, physical activity and behavioral interventions). Expression of genes involved in the inflammasome pathway, plasma concentration of the inflammasome-associated pro-inflammatory cytokines (interleukin (IL)-1β and IL-18) and indexes of microbial translocation (lipopolysaccharide (LPS), soluble CD14 (sCD14) and intestinal fatty acid-binding protein) were analyzed at baseline in obese subjects compared with controls, and after 18 months in obese subjects.
  
  
  
  Cross-sectional analyses showed that the LPS-induced expression of genes involved in inflammasome (NLRP3, caspase 5 and NAIP), Nod-like receptors (NLRX1 and NOD1), downstream signaling (P2RX7, RAGE, RIPk2, TIRAP and BIRC2) and effector molecules (IFN-γ, IL-12β, IL-1β, CCL2, CCL5, IL-6 and TNFα) was significantly increased in obese subjects at baseline as compared with normal weight controls. The baseline plasma concentration of inflammasome-related cytokines (IL-1β and IL-18) and of microbial translocation markers (LPS and sCD14) was augmented in obese subjects as compared with controls as well. Longitudinal analyses indicated that intensive lifestyle modification resulted in a normalization of parameters in subjects with a significant reduction of BMI after 18 months.
  
  
  
  In children and adolescents, obesity is characterized by the activation of the inflammasome and by an alteration of gut permeability. Successful lifestyle modification is effective in reducing inflammation, suggesting that inhibition of the inflammasome may be a potential therapeutic strategy in obesity.
authors.affiliation: Department of Biomedical and Clinical Sciences 'L. Sacco', University of Milan, Milan, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Rainone
authors.affiliation: Department of Pediatrics, University of Milan, L. Sacco Hospital, Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Schneider
authors.affiliation: Department of Biomedical and Clinical Sciences 'L. Sacco', University of Milan, Milan, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Saulle
authors.affiliation: Department of Preventive Medicine and Epidemiology, University of Regensburg, Regensburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Ricci
authors.affiliation: Department of Biomedical and Clinical Sciences 'L. Sacco', University of Milan, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Biasin
authors.affiliation: Biomarkers Research Program, Biochemistry Department, College of Science, King Saud University, Riyadh, Saudi Arabia.|Prince Mutaib Chair for Biomarkers of Osteoporosis, King Saud University, Riyadh, Saudi Arabia.
authors.forename: N M
authors.initials: NM
authors.lastname: Al-Daghri
authors.affiliation: Department of Pediatrics, University of Milan, Ospedale dei Bambini V. Buzzi, Milan, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Giani
authors.affiliation: Department of Pediatrics, University of Milan, L. Sacco Hospital, Milan, Italy.|Department of Pediatrics, University of Milan, Ospedale dei Bambini V. Buzzi, Milan, Italy.
authors.forename: G V
authors.initials: GV
authors.lastname: Zuccotti
authors.affiliation: Department of Medical-Surgery Physiopathology and Transplantation, University of Milan, Milan, Italy.|Don C. Gnocchi Foundation ONLUS, IRCCS, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Clerici
authors.affiliation: Department of Biomedical and Clinical Sciences 'L. Sacco', University of Milan, Milan, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Trabattoni
mesh_terms: D050156:Adipogenesis; D000293:Adolescent; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000517:prevention & control*; D002352:Carrier Proteins / Q000378:metabolism; D002648:Child; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000517:prevention & control*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D007408:Intestinal Absorption / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D050152:Intra-Abdominal Fat / Q000378:metabolism*; D007558:Italy / Q000453:epidemiology; D008137:Longitudinal Studies; D008264:Macrophages / Q000378:metabolism; D008297:Male; D063766:Pediatric Obesity / Q000453:epidemiology / Q000378:metabolism* / Q000517:prevention & control; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes