title: Adipose Tissue-Derived Stem Cells From Obese Subjects Contribute to Inflammation and Reduced Insulin Response in Adipocytes Through Differential Regulation of the Th1/Th17 Balance and Monocyte Activation.
abstract: Obesity, through low-grade inflammation, can drive insulin resistance and type 2 diabetes. While infiltration of adipose tissue (AT) with mononuclear cells (MNCs) is well established in obesity, the functional consequences of these interactions are less understood. Herein, we cocultured human adipose-derived stem cells (ASCs) from obese individuals with MNCs and analyzed their reciprocal behavior. Presence of ASCs 1) enhanced interleukin (IL)-17A secretion by Th17 cells, 2) inhibited γ-interferon and tumor necrosis factor α secretion by Th1 cells, and 3) increased monocyte-mediated IL-1β secretion. IL-17A secretion also occurred in stromal vascular fractions issued from obese but not lean individuals. Th17 polarization mostly depended on physical contacts between ASCs and MNCs-with a contribution of intracellular adhesion molecule-1-and occurred through activation of the inflammasome and phosphatidylinositol 3-kinase pathways. ASCs favored STAT3 over STAT5 transcription factor binding on STAT binding sites within the IL-17A/F gene locus. Finally, conditioned media from activated ASC-MNC cocultures inhibited adipocyte differentiation mRNA markers and impaired insulin-mediated Akt phosphorylation and lipolysis inhibition. In conclusion, we report that obese- but not lean-derived ASCs induce Th17 promotion and monocyte activation. This proinflammatory environment, in turn, inhibits adipogenesis and adipocyte insulin response. The demonstration of an ASC-Th17-monocyte cell axis reveals a novel proinflammatory process taking place in AT during obesity and defines novel putative therapeutic targets.
authors.affiliation: CarMeN Laboratory, INSERM U1060, Lyon-1 University, INRA U1397, INSA-Lyon, Lyon, France Clinical Research Department, Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France assia.eljaafari@univ-lyon1.fr luciano.pirola@univ-lyon1.fr.
authors.forename: Assia
authors.initials: A
authors.lastname: Eljaafari
authors.affiliation: CarMeN Laboratory, INSERM U1060, Lyon-1 University, INRA U1397, INSA-Lyon, Lyon, France Gastroenterology and Surgery Department, Edouard Herriot Hospital, Lyon, France.
authors.forename: Maud
authors.initials: M
authors.lastname: Robert
authors.affiliation: CarMeN Laboratory, INSERM U1060, Lyon-1 University, INRA U1397, INSA-Lyon, Lyon, France.
authors.forename: Marwa
authors.initials: M
authors.lastname: Chehimi
authors.affiliation: CarMeN Laboratory, INSERM U1060, Lyon-1 University, INRA U1397, INSA-Lyon, Lyon, France.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Chanon
authors.affiliation: CarMeN Laboratory, INSERM U1060, Lyon-1 University, INRA U1397, INSA-Lyon, Lyon, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Durand
authors.affiliation: CarMeN Laboratory, INSERM U1060, Lyon-1 University, INRA U1397, INSA-Lyon, Lyon, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Vial
authors.affiliation: CarMeN Laboratory, INSERM U1060, Lyon-1 University, INRA U1397, INSA-Lyon, Lyon, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Bendridi
authors.affiliation: CarMeN Laboratory, INSERM U1060, Lyon-1 University, INRA U1397, INSA-Lyon, Lyon, France.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Madec
authors.affiliation: CarMeN Laboratory, INSERM U1060, Lyon-1 University, INRA U1397, INSA-Lyon, Lyon, France Clinical Research Department, Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Disse
authors.affiliation: CarMeN Laboratory, INSERM U1060, Lyon-1 University, INRA U1397, INSA-Lyon, Lyon, France Clinical Research Department, Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France.
authors.forename: Martine
authors.initials: M
authors.lastname: Laville
authors.affiliation: CarMeN Laboratory, INSERM U1060, Lyon-1 University, INRA U1397, INSA-Lyon, Lyon, France.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rieusset
authors.affiliation: CarMeN Laboratory, INSERM U1060, Lyon-1 University, INRA U1397, INSA-Lyon, Lyon, France.
authors.forename: Etienne
authors.initials: E
authors.lastname: Lefai
authors.affiliation: CarMeN Laboratory, INSERM U1060, Lyon-1 University, INRA U1397, INSA-Lyon, Lyon, France.
authors.forename: Hubert
authors.initials: H
authors.lastname: Vidal
authors.affiliation: CarMeN Laboratory, INSERM U1060, Lyon-1 University, INRA U1397, INSA-Lyon, Lyon, France assia.eljaafari@univ-lyon1.fr luciano.pirola@univ-lyon1.fr.
authors.forename: Luciano
authors.initials: L
authors.lastname: Pirola
mesh_terms: D017667:Adipocytes / Q000502:physiology*; D000273:Adipose Tissue / Q000166:cytology*; D000818:Animals; D002450:Cell Communication; D007249:Inflammation / Q000209:etiology*; D007328:Insulin / Q000494:pharmacology*; D020381:Interleukin-17 / Q000096:biosynthesis / Q000235:genetics; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009000:Monocytes / Q000502:physiology*; D009765:Obesity / Q000150:complications* / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D050791:STAT Transcription Factors / Q000502:physiology; D013234:Stem Cells / Q000502:physiology*; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D007328:Insulin; D020381:Interleukin-17; D053583:Interleukin-1beta; D015850:Interleukin-6; D050791:STAT Transcription Factors; D019869:Phosphatidylinositol 3-Kinases