title: Pathologic endoplasmic reticulum stress induced by glucotoxic insults inhibits adipocyte differentiation and induces an inflammatory phenotype.
abstract: Adipocyte differentiation is critical in obesity. By controlling new adipocyte recruitment, adipogenesis contrasts adipocyte hypertrophy and its adverse consequences, such as insulin resistance. Contrasting data are present in literature on the effect of endoplasmic reticulum (ER) stress and subsequent unfolded protein response (UPR) on adipocyte differentiation, being reported to be either necessary or inhibitory. In this study, we sought to clarify the effect of ER stress and UPR on adipocyte differentiation. We have used two different cell lines, the widely used pre-adipocyte 3T3-L1 cells and a murine multipotent mesenchymal cell line, W20-17 cells. A strong ER stress activator, thapsigargin, and a pathologically relevant inducer of ER stress, glucosamine (GlcN), induced ER stress and UPR above those occurring in the absence of perturbation and inhibited adipocyte differentiation. Very low concentrations of 4-phenyl butyric acid (PBA, a chemical chaperone) inhibited only the overactivation of ER stress and UPR elicited by GlcN, leaving unaltered the part physiologically activated during differentiation, and reversed the inhibitory effect of GlcN on differentiation. In addition, GlcN stimulated proinflammatory cytokine release and PBA prevented these effects. An inhibitor of NF-kB also reversed the effects of GlcN on cytokine release. These results indicate that while ER stress and UPR activation is "physiologically" activated during adipocyte differentiation, the "pathologic" part of ER stress activation, secondary to a glucotoxic insult, inhibits differentiation. In addition, such a metabolic insult, causes a shift of the preadipocyte/adipocyte population towards a proinflammatory phenotype.
authors.affiliation: Dipartimento di Scienze Mediche Traslazionali, Università "Federico II", °IEOS/CNR, via S. Pansini 5, 80131 Napoli, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Longo
authors.affiliation: Dipartimento di Scienze Mediche Traslazionali, Università "Federico II", °IEOS/CNR, via S. Pansini 5, 80131 Napoli, Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: Spinelli
authors.affiliation: Dipartimento di Scienze Mediche Traslazionali, Università "Federico II", °IEOS/CNR, via S. Pansini 5, 80131 Napoli, Italy.
authors.forename: Vittoria
authors.initials: V
authors.lastname: D'Esposito
authors.affiliation: Dipartimento di Scienze Mediche Traslazionali, Università "Federico II", °IEOS/CNR, via S. Pansini 5, 80131 Napoli, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Zatterale
authors.affiliation: Dipartimento di Scienze Mediche Traslazionali, Università "Federico II", °IEOS/CNR, via S. Pansini 5, 80131 Napoli, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Fiory
authors.affiliation: Dipartimento di Scienze Mediche Traslazionali, Università "Federico II", °IEOS/CNR, via S. Pansini 5, 80131 Napoli, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Nigro
authors.affiliation: Dipartimento di Scienze Mediche Traslazionali, Università "Federico II", °IEOS/CNR, via S. Pansini 5, 80131 Napoli, Italy.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Raciti
authors.affiliation: Dipartimento di Scienze Mediche Traslazionali, Università "Federico II", °IEOS/CNR, via S. Pansini 5, 80131 Napoli, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Miele
authors.affiliation: Dipartimento di Scienze Mediche Traslazionali, Università "Federico II", °IEOS/CNR, via S. Pansini 5, 80131 Napoli, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Formisano
authors.affiliation: Dipartimento di Scienze Mediche Traslazionali, Università "Federico II", °IEOS/CNR, via S. Pansini 5, 80131 Napoli, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Beguinot
authors.affiliation: Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento, Strada Monteroni, 73100 Lecce, Italy. Electronic address: bruno.dijeso@unisalento.it.
authors.forename: Bruno
authors.initials: B
authors.lastname: Di Jeso
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000328:Adult; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D015870:Gene Expression / Q000187:drug effects; D005944:Glucosamine / Q000494:pharmacology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D051379:Mice; D008875:Middle Aged; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010641:Phenotype; D010654:Phenylbutyrates / Q000494:pharmacology; D010655:Phenylenediamines / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019284:Thapsigargin / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects / Q000235:genetics / Q000502:physiology
chemical_list: C549066:4-methyl-N1-(3-phenylpropyl)benzene-1,2-diamine; D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D010654:Phenylbutyrates; D010655:Phenylenediamines; D019284:Thapsigargin; C075773:4-phenylbutyric acid; D005944:Glucosamine
keywords: Adipocyte differentiation; ER stress; Inflammation