title: Adipocyte differentiation induces dynamic changes in NF-kappaB expression and activity.
abstract: The adipocyte exerts an important role in energy homeostasis, both as depot for energy-rich triglycerides and as a source for metabolic hormones. Adipocytes also contribute to inflammation and the innate immune response. Although it can be physiologically beneficial to combine these two functions in a single cell type under some circumstances, the proinflammatory signals emanating from adipocytes in the obese state can have local and systemic effects that promote atherosclerosis and insulin resistance. The transcriptional machinery in the adipocyte that mediates these pro-inflammatory responses has remained poorly characterized to date. In particular, no information is currently available on the NF-kappaB family of transcription factors. Here, we show that adipogenesis is associated with changes in amount and subunit composition of the NF-kappaB complexes. NF-kappaB subunits p65 (RelA), p68 (RelB), and IkappaB are upregulated during fat cell differentiation. Correspondingly, basal NF-kappaB nuclear gel shift and luciferase reporter assays are induced in parallel during differentiation. Surprisingly, endotoxin sensitivity of the classical NF-kappaB pathway is substantially delayed and attenuated despite increased overall inflammatory response in the mature adipocyte, as judged by induction of IL-6 and TNF-alpha. As a reflection of the constitutively elevated NF-kappaB activity in the mature adipocyte, adipocytes (but not preadipocytes) exert a strong inflammatory stimulus on macrophages in vitro, suggesting a cross talk between adipocytes and interstitial macrophages in adipose tissue in vivo. These effects are mediated by a secretory product of adipocytes that is unlikely to be IL-6 or TNF-alpha.
authors.affiliation: Dept. of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, New York, NY 10461, USA.
authors.forename: Anders H
authors.initials: AH
authors.lastname: Berg
authors.forename: Ying
authors.initials: Y
authors.lastname: Lin
authors.forename: Michael P
authors.initials: MP
authors.lastname: Lisanti
authors.forename: Philipp E
authors.initials: PE
authors.lastname: Scherer
mesh_terms: D016475:3T3 Cells; D021581:Active Transport, Cell Nucleus; D017667:Adipocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008156:Luciferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008264:Macrophages / Q000502:physiology; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D013234:Stem Cells / Q000201:enzymology; D051996:Transcription Factor RelA; D051841:Transcription Factor RelB; D014157:Transcription Factors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D020672:I-kappa B Proteins; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; C497594:Relb protein, mouse; D051996:Transcription Factor RelA; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D051841:Transcription Factor RelB; D004247:DNA; D008156:Luciferases