title: Classical and alternative NF-κB signaling cooperate in regulating adipocyte differentiation and function.
abstract: OBJECTIVE
  Inflammation of adipose tissue (AT) is a central mediator of insulin resistance. However, the molecular mechanisms triggered by inflammatory cells are not fully understood. The aim of this study was to analyze the metabolic functions of lymphotoxin-β-receptor (LTβR)-mediated alternative NF-κB signaling in adipocytes and to reveal its effects on body weight and insulin sensitivity in vivo.
  
  
  METHODS
  RelB(FatKO) mice and littermate controls were treated with LTβR agonistic antibody (α-LTβR) or a LTβR antagonist (LTβR:Ig fusion protein) after feeding a high-fat diet or standard diet. Mice were analyzed by insulin tolerance and glucose tolerance tests prior to analysis by necropsy and qRT-PCR of abdominal white adipose tissue. 3T3-L1 preadipocytes and mouse embryonic fibroblasts were used for differentiation and expression analysis after treatment with α-LTβR and differentiation to adipocytes. The molecular mechanism was elucidated by chromatin immunoprecipitation and combinatorial treatment with α-LTβR and tumor necrosis factor (TNF).
  
  
  RESULTS
  RelB(FatKO) mice showed improved insulin sensitivity despite increased adiposity and adipocyte hypertrophy. LTβR-induced activation of p52-RelB in 3T3-L1 cells attenuated adipogenesis and modulated adipocyte functions via transcriptional downregulation of peroxisome proliferator-activated receptor γ (PPARγ). This LTβR-mediated pathway was synergistically regulated via a TNF-induced increase in p100 and RelB expression and nuclear translocation.
  
  
  CONCLUSIONS
  Our data describe an anti-adipogenic action of LTβR signaling and a novel synergism of alternative and classical NF-κB signaling in the regulation of adipocytes. In conclusion, this strong synergism between the two NF-κB pathways shows a method to inhibit adipocyte differentiation and to improve insulin sensitivity and can be a potential target to treat metabolic disorders more efficiently than with other known drugs.
authors.affiliation: Immunology, Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Jena, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Weidemann
authors.affiliation: Immunology, Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Jena, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Lovas
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.
authors.forename: A
authors.initials: A
authors.lastname: Rauch
authors.affiliation: Immunology, Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Jena, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Andreas
authors.affiliation: Immunology, Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Jena, Germany.
authors.forename: J
authors.initials: J
authors.lastname: von Maltzahn
authors.affiliation: Immunology, Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Jena, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Riemann
authors.affiliation: Immunology, Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Jena, Germany.|Faculty of Biology and Pharmacology, Friedrich-Schiller-University Jena, Jena, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Weih
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism*; D050156:Adipogenesis; D000818:Animals; D002454:Cell Differentiation; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D015151:Immunoblotting; D053259:Lymphotoxin beta Receptor / Q000378:metabolism*; D053308:Lymphotoxin-beta / Q000494:pharmacology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction; D051841:Transcription Factor RelB / Q000378:metabolism*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha; D015854:Up-Regulation
chemical_list: C505699:Ltbr protein, mouse; D053259:Lymphotoxin beta Receptor; D053308:Lymphotoxin-beta; D016328:NF-kappa B; C497594:Relb protein, mouse; D014409:Tumor Necrosis Factor-alpha; D051841:Transcription Factor RelB