title: NF-kappaB is important for TNF-alpha-induced lipolysis in human adipocytes.
abstract: Tumor necrosis factor-alpha (TNF-alpha) promotes lipolysis in mammal adipocytes via the mitogen-activated protein kinase (MAPK) family, resulting in reduced expression/function of perilipin (PLIN). The role of another pivotal intracellular messenger activated by TNF-alpha, nuclear factor-kappaB (NF-kappaB), has not been recognized. We explored the role of NF-kappaB in TNF-alpha-induced lipolysis of human fat cells. Primary cultures of human adipocytes were incubated in the presence of a cell-permeable peptide that inhibits NF-kappaB signaling (WP). Incubation with WP, but not with a biologically inactive peptide (MP), abolished the nuclear translocation of NF-kappaB and effectively abrogated TNF-alpha-induced lipolysis in a concentration-dependent manner. Western blot analysis demonstrated that although TNF-alpha per se reduced mainly PLIN protein expression, TNF-alpha in the presence of WP resulted in a pronounced combined reduction of both hormone-sensitive lipase (HSL) and PLIN protein. The expression of a set of other lipolytic or adipocyte-specific proteins was not affected. The regulation was presumably at the transcriptional level, because mRNA expression for HSL and PLIN was markedly reduced with TNF-alpha in the presence of NF-kappaB inhibition. This was confirmed in gene reporter assays using human PLIN and HSL promoter constructs. We conclude that in the presence of NF-kappaB inhibition, TNF-alpha-mediated lipolysis is reduced, which suggests that NF-kappaB is essential for retained human fat cell lipolysis.
authors.affiliation: Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, 141 86 Stockholm, Sweden.
authors.forename: Jurga
authors.initials: J
authors.lastname: Laurencikiene
authors.forename: Vanessa
authors.initials: V
authors.lastname: van Harmelen
authors.forename: Elisabet
authors.initials: E
authors.lastname: Arvidsson Nordström
authors.forename: Andrea
authors.initials: A
authors.lastname: Dicker
authors.forename: Lennart
authors.initials: L
authors.lastname: Blomqvist
authors.forename: Erik
authors.initials: E
authors.lastname: Näslund
authors.forename: Dominique
authors.initials: D
authors.lastname: Langin
authors.forename: Peter
authors.initials: P
authors.lastname: Arner
authors.forename: Mikael
authors.initials: M
authors.lastname: Rydén
mesh_terms: D021581:Active Transport, Cell Nucleus; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism*; D002352:Carrier Proteins; D002463:Cell Membrane Permeability / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation; D006801:Humans; D008066:Lipolysis / Q000187:drug effects*; D016328:NF-kappa B / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D000070778:Perilipin-1; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction; D014158:Transcription, Genetic / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D002352:Carrier Proteins; D016328:NF-kappa B; D010455:Peptides; D000070778:Perilipin-1; D010750:Phosphoproteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha