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.

Eljaafari A, Robert M, Chehimi M, Chanon S, Durand C, Vial G, Bendridi N, Disse E, Laville M, Rieusset J, Lefai E, Vidal H, Pirola L

Obesity, through low-grade inflammation, can drive insulin-resistance and type 2 diabetes. While infiltration of adipose tissue (AT) with mononuclear cells (MNC) is well established in obesity, the functional consequences of these interactions are less understood.Herein, we co-cultured human adipose-derived-stem cells (ASC) from obese individuals with MNC and analyzed their reciprocal behavior. Presence of ASC (i) enhanced IL-17A secretion by Th17 cells, (ii) inhibited IFNγ and TNFα secretion by Th1 cells and (iii) 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 ASC and MNC - with a contribution of ICAM-1 adhesion molecules - and occurred through activation of the inflammasome and phosphoinositide-3-kinase pathways. ASC favored STAT3 over STAT5 transcription factor binding on STAT binding sites within the IL17A/F gene locus. Finally, conditioned media from activated ASC-MNC co-cultures inhibited adipocyte differentiation mRNA markers, impaired insulin-mediated Akt phosphorylation and lipolysis inhibition.In conclusion, we report that obese- but not lean-derived ASC induce Th17 promotion and monocyte activation. This pro-inflammatory environment, in turn, inhibits adipogenesis and adipocyte insulin response. The demonstration of an ASC-Th17-monocyte cell axis reveals a novel pro-inflammatory process taking place in adipose tissue during obesity, and defines novel putative therapeutic targets.

Chromatin Shearing

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March, 2015



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