title: A Role of the Inflammasome in the Low Storage Capacity of the Abdominal Subcutaneous Adipose Tissue in Obese Adolescents.
abstract: The innate immune cell sensor leucine-rich-containing family, pyrin domain containing 3 (NLRP3) inflammasome controls the activation of caspase-1, and the release of proinflammatory cytokines interleukin (IL)-1β and IL-18. The NLRP3 inflammasome is implicated in adipose tissue inflammation and the pathogenesis of insulin resistance. Herein, we tested the hypothesis that adipose tissue inflammation and NLRP3 inflammasome are linked to the downregulation of subcutaneous adipose tissue (SAT) adipogenesis/lipogenesis in obese adolescents with altered abdominal fat partitioning. We performed abdominal SAT biopsies on 58 obese adolescents and grouped them by MRI-derived visceral fat to visceral adipose tissue (VAT) plus SAT (VAT/VAT+SAT) ratio (cutoff 0.11). Adolescents with a high VAT/VAT+SAT ratio showed higher SAT macrophage infiltration and higher expression of the NLRP3 inflammasome-related genes (i.e., TLR4, NLRP3, IL1B, and CASP1). The increase in inflammation markers was paralleled by a decrease in genes related to insulin sensitivity (ADIPOQ, GLUT4, PPARG2, and SIRT1) and lipogenesis (SREBP1c, ACC, LPL, and FASN). Furthermore, SAT ceramide concentrations correlated with the expression of CASP1 and IL1B. Infiltration of macrophages and upregulation of the NLRP3 inflammasome together with the associated high ceramide content in the plasma and SAT of obese adolescents with a high VAT/VAT+SAT may contribute to the limited expansion of the subcutaneous abdominal adipose depot and the development of insulin resistance.
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, CT.
authors.forename: Romy
authors.initials: R
authors.lastname: Kursawe
authors.affiliation: Section of Comparative Medicine, Yale Program in Integrative Cell Signaling and Neurobiology of Metabolism, and Department of Immunobiology, Yale University School of Medicine, New Haven, CT.
authors.forename: Vishwa D
authors.initials: VD
authors.lastname: Dixit
authors.affiliation: Internal Medicine, Touchstone Diabetes Center, The University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Philipp E
authors.initials: PE
authors.lastname: Scherer
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, CT.
authors.forename: Nicola
authors.initials: N
authors.lastname: Santoro
authors.affiliation: Department of Plastic Surgery, Yale University School of Medicine, New Haven, CT.
authors.forename: Deepak
authors.initials: D
authors.lastname: Narayan
authors.affiliation: Internal Medicine, Touchstone Diabetes Center, The University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Ruth
authors.initials: R
authors.lastname: Gordillo
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, CT.
authors.forename: Cosimo
authors.initials: C
authors.lastname: Giannini
authors.affiliation: Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas, TX.
authors.forename: Ximena
authors.initials: X
authors.lastname: Lopez
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, CT.
authors.forename: Bridget
authors.initials: B
authors.lastname: Pierpont
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, CT.
authors.forename: Jessica
authors.initials: J
authors.lastname: Nouws
authors.affiliation: Department of Internal Medicine, Yale University School of Medicine, New Haven, CT Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT Howard Hughes Medical Institute, Chevy Chase, MD.
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
authors.affiliation: Department of Pediatrics, Yale University School of Medicine, New Haven, CT sonia.caprio@yale.edu.
authors.forename: Sonia
authors.initials: S
authors.lastname: Caprio
mesh_terms: D000005:Abdomen; D000103:Acetyl-CoA Carboxylase / Q000235:genetics / Q000378:metabolism; D050156:Adipogenesis / Q000235:genetics*; D052242:Adiponectin / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D002352:Carrier Proteins / Q000235:genetics* / Q000276:immunology; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D002648:Child; D015536:Down-Regulation; D054890:Fatty Acid Synthase, Type I / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D058847:Inflammasomes; D007333:Insulin Resistance; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D050152:Intra-Abdominal Fat / Q000378:metabolism* / Q000473:pathology; D020738:Leptin / Q000378:metabolism; D050155:Lipogenesis / Q000235:genetics*; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D008279:Magnetic Resonance Imaging; D008297:Male; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009765:Obesity / Q000276:immunology / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D050151:Subcutaneous Fat / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism
chemical_list: C499918:ADIPOQ protein, human; D052242:Adiponectin; D002352:Carrier Proteins; D051275:Glucose Transporter Type 4; C508585:IL1B protein, human; D058847:Inflammasomes; D053583:Interleukin-1beta; D020738:Leptin; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D047495:PPAR gamma; C495692:SLC2A4 protein, human; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I; C548261:LPL protein, human; D008071:Lipoprotein Lipase; D020170:Caspase 1; C447939:SIRT1 protein, human; D056564:Sirtuin 1; C000588423:ACACA protein, human; D000103:Acetyl-CoA Carboxylase