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

• Published in: Diabetes (New York, N.Y.) Vol. 64; no. 7; pp. 2477 - 2488
• Main Authors: Eljaafari, Assia, Robert, Maud, Chehimi, Marwa, Chanon, Stephanie, Durand, Christine, Vial, Guillaume, Bendridi, Nadia, Madec, Anne-Marie, Disse, Emmanuel, Laville, Martine, Rieusset, Jennifer, Lefai, Etienne, Vidal, Hubert, Pirola, Luciano
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.07.2015
• Subjects: Adipocytes - physiology; Adipose Tissue - cytology; Animals; Binding sites; Cell Communication; Cells; Inflammation - etiology; Insulin - pharmacology; Insulin resistance; Interleukin-17 - biosynthesis; Interleukin-17 - genetics; Interleukin-1beta - secretion; Interleukin-6 - secretion; Life Sciences; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Monocytes - physiology; Obesity; Obesity - complications; Obesity - immunology; Phosphatidylinositol 3-Kinases - physiology; Phosphorylation; STAT Transcription Factors - physiology; Stem Cells - physiology; Th1 Cells - immunology; Th17 Cells - immunology; Stem Cells/physiology; Obese; Interleukin-17/biosynthesis/genetics; Cell Communication; Male; Interleukin-1beta/secretion; Phosphatidylinositol 3-Kinases/physiology; Inbred C57BL; Obesity/complications/immunology; STAT Transcription Factors/physiology; Insulin/pharmacology; Monocytes/physiology; Animals; Inflammation/etiology; Interleukin-6/secretion; Adipose Tissue/cytology; Th17 Cells/immunology; Mice; Th1 Cells/immunology; Adipocytes/physiology
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db15-0162

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.