title: Effects of TWEAK (TNF superfamily member 12) on differentiation, metabolism, and secretory function of human primary preadipocytes and adipocytes.
abstract: Expansion of adipose tissue mass by hypertrophy and hyperplasia is the hallmark of obesity. An automated cDNA screen was established to identify secreted human proteins with an inhibitory effect on adipocyte differentiation and, thereby, a potential inhibitory effect on adipose tissue growth. A member of the TNF superfamily, TNF-like weak inducer of apoptosis (TWEAK; TNF superfamily 12) was identified by means of high-throughput screening with the lipophilic dye Nile Red as an inhibitor of murine adipocyte differentiation and, subsequently, also of human adipocyte differentiation. TWEAK inhibited lipid deposition in a dose-dependent manner without causing cytotoxic effects. This inhibitory action was mimicked by an agonistic antibody of the TWEAK receptor. The TWEAK receptor (fibroblast growth factor inducible 14; CD266) was expressed on human primary preadipocytes and mature adipocytes. Knockdown of TWEAK receptor by short-hairpin RNA abolished the inhibitory effect of TWEAK on cell differentiation, demonstrating that the effects of TWEAK are mediated by its specific receptor. Inhibition of differentiation was the result of interference at an early step of transcriptional activation as assessed by decreased peroxisome proliferator-activated receptor-gamma, CCAAT enhancer-binding protein alpha (C/EBPalpha), and CCAAT enhancer-binding protein beta (C/EBPbeta) mRNA expression. In contrast to TNFalpha, basal and insulin-stimulated glucose uptake and lipolysis of terminally differentiated mature adipocytes and secretion of proinflammatory cytokines were not altered in the presence of TWEAK, and nuclear factor kappa B activity was only weakly induced. We conclude from our findings that TWEAK and the corresponding agonistic antibody have the potential to prevent adipose tissue growth without adversely influencing central metabolic pathways or proinflammatory cytokine secretion in adipose tissue.
authors.affiliation: Else Kröner-Fresenius-Zentrum für Ernährungsmedizin, Technische Universität München, 85350 Freising, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Tiller
authors.forename: Pamela
authors.initials: P
authors.lastname: Fischer-Posovszky
authors.forename: Helmut
authors.initials: H
authors.lastname: Laumen
authors.forename: Andreas
authors.initials: A
authors.lastname: Finck
authors.forename: Thomas
authors.initials: T
authors.lastname: Skurk
authors.forename: Michaela
authors.initials: M
authors.lastname: Keuper
authors.forename: Ulrich
authors.initials: U
authors.lastname: Brinkmann
authors.forename: Martin
authors.initials: M
authors.lastname: Wabitsch
authors.forename: Dieter
authors.initials: D
authors.lastname: Link
authors.forename: Hans
authors.initials: H
authors.lastname: Hauner
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D052242:Adiponectin / Q000235:genetics; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D002478:Cells, Cultured; D000074049:Cytokine TWEAK; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D015723:Gene Library; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects*; D051379:Mice; D047495:PPAR gamma / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D000074050:TWEAK Receptor; D013997:Time Factors; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D052242:Adiponectin; D022763:CCAAT-Enhancer-Binding Protein-alpha; D022782:CCAAT-Enhancer-Binding Protein-beta; D000074049:Cytokine TWEAK; D015850:Interleukin-6; D047495:PPAR gamma; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors; D007371:Interferon-gamma