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

A. Eljaafari , M. Robert , M. Chehimi , S. Chanon , C. Durand , G. Vial , N. Bendridi , A. M. Madec , E. Disse , M. Laville , Jennifer Rieusset (1) , Etienne Lefai , Hubert Vidal , L. Pirola

1 CarMeN - Cardiovasculaire, métabolisme, diabétologie et nutrition

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 gamma-interferon and tumor necrosis factor alpha secretion by Th1 cells, and 3) increased monocyte-mediated IL-1beta 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.

Mots clés: Male; Animals; Mice; Inbred C57BL; Insulin/*pharmacology; Adipocytes/*physiology; Adipose Tissue/*cytology; Cell Communication; Inflammation/*etiology; Interleukin-17/biosynthesis/genetics; Interleukin-1beta/secretion; Interleukin-6/secretion; Obese; Monocytes/*physiology; Obesity/*complications/immunology; Stem Cells/*physiology; Th1 Cells/*immunology; Th17 Cells/*immunology; Phosphatidylinositol 3-Kinases/physiology; STAT Transcription Factors/physiology

Domaines: Sciences du Vivant [q-bio]

A. Eljaafari, M. Robert, M. Chehimi, S. Chanon, C. Durand, et al.. 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. Diabetes, 2015, 64 (7), pp.2477-88. ⟨10.2337/db15-0162⟩. ⟨hal-01850502⟩