title: TNF-related apoptosis-inducing ligand promotes human preadipocyte proliferation via ERK1/2 activation.
abstract: Upon obesity, adipose tissue is excessively expanded and characterized by pathologic processes like hypoxia, fibrosis, and inflammation. Death ligands belonging to the TNF superfamily such as TNF-α are important contributors to these derangements and exert a pronounced influence on the metabolic and cellular homeostasis of adipose tissue. Here, we sought to identify the effect of the death ligand TNF-related apoptosis-inducing ligand (TRAIL) on the adipose tissue precursor cell pool and therefore investigated its influence on preadipocyte proliferation. Treatment of human preadipocytes with TRAIL resulted in a time- and dose-dependent increase in proliferation (EC50 3.4 ng/ml) comparable to IGF-1. Although no apoptosis was observed, TRAIL triggered a rapid cleavage of caspase-8 and -3. Neither inhibition of caspase activity by zVAD.fmk (20 µM) nor ablation of caspase-8 expression by lentivirus-delivered small hairpin RNA (shRNA) abolished the proliferative response. TRAIL triggered a delayed and sustained activation of ERK1/2, leaving Akt, p38, JNK, and NF-κB unaffected. Importantly, inhibition of ERK1/2 activation by PD0325901 (300 nM) or AZD6244 (5 or 10 µM) completely abolished the proliferative response. We thus reveal a hitherto unknown function of TRAIL in regulating adipose tissue homeostasis by promoting the proliferation of tissue-resident precursor cells.
authors: *Division of Pediatric Endocrinology and Diabetes and Department of Pediatrics and Adolescent Medicine, Ulm Medical Center, Ulm, Germany.
authors: Jan-Bernd
authors: JB
authors: Funcke
authors: *Division of Pediatric Endocrinology and Diabetes and Department of Pediatrics and Adolescent Medicine, Ulm Medical Center, Ulm, Germany.
authors: Verena
authors: V
authors: Zoller
authors: *Division of Pediatric Endocrinology and Diabetes and Department of Pediatrics and Adolescent Medicine, Ulm Medical Center, Ulm, Germany.
authors: Muad Abd
authors: MA
authors: El Hay
authors: *Division of Pediatric Endocrinology and Diabetes and Department of Pediatrics and Adolescent Medicine, Ulm Medical Center, Ulm, Germany.
authors: Klaus-Michael
authors: KM
authors: Debatin
authors: *Division of Pediatric Endocrinology and Diabetes and Department of Pediatrics and Adolescent Medicine, Ulm Medical Center, Ulm, Germany.
authors: Martin
authors: M
authors: Wabitsch
authors: *Division of Pediatric Endocrinology and Diabetes and Department of Pediatrics and Adolescent Medicine, Ulm Medical Center, Ulm, Germany pamela.fischer@uniklinik-ulm.de.
authors: Pamela
authors: P
authors: Fischer-Posovszky
mesh_terms: D052438:Adipocytes, White / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D000328:Adult; D053687:Adult Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D001145:Arrhythmias, Cardiac / Q000378:metabolism / Q000473:pathology; D001549:Benzamides / Q000494:pharmacology; D001562:Benzimidazoles / Q000494:pharmacology; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000378:metabolism / Q000473:pathology; D005877:Gigantism / Q000378:metabolism / Q000473:pathology; D006330:Heart Defects, Congenital / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008607:Intellectual Disability / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012313:RNA / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism* / Q000494:pharmacology
chemical_list: C517975:AZD 6244; D001549:Benzamides; D001562:Benzimidazoles; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; C039919:RNA, recombinant; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D012313:RNA; C506614:mirdametinib; D004159:Diphenylamine; D051057:Proto-Oncogene Proteins c-akt; C505530:CASP8 protein, human; D053181:Caspase 8
keywords: adipocyte progenitor; adipose tissue homeostasis; death ligand; noncanonical signaling