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.

Beneficial Effects of Fasting on White Adipose Tissue Inflammation and Metabolic Syndrome in Obese Subjects: Review

“…Accordingly, insulin sensitivity was improved, together with decreased blood glucose levels, in a 6 months twice-weekly CR diet [33]. IL-17A secretion is also increased in obese WAT, as reported by us and others [10,14,15,17,18]. Therefore, using our previously experimental model able to promote Th17 cell activation in obese WAT [17], we analyzed the effects of overnight fasting in genetically modified ob/ob mice and observed a marked reduction in IL-17A secretion ( Figure 1B), suggesting that shortterm fasting can be sufficient enough to inhibit Th17 cell activation in WAT.…”

“…ASC-mediated lL-17A secretion was associated with increased secretion of IL-1β by monocytes and IL-6 by ASC ( Figure 1A). Interestingly, IL-17A secretion was also found to be increased in the stromal vascular fractions (SVF) of obese, but not lean subjects [17,18]. …”

“…IL-17A has also been suggested to favor the development of insulin resistance, through down-regulation of multiple pro-adipogenic transcription factor expression, such as PPARγ, C/EBPα, leading to inhibition of adipogenesis [16]. Recently, we have reported that adipose stem cells (ASC) from obese, but not lean donors, contribute to Th17 promotion through contact-dependent interactions and soluble factor secretion [17]. ASC-mediated lL-17A secretion was associated with increased secretion of IL-1β by monocytes and IL-6 by ASC ( Figure 1A).…”

Revisiting the adipocyte: a model for integration of cytokine signaling in the regulation of energy metabolism

“…Adipose tissue-infiltrated CD4 ϩ and CD8 ϩ T cells also produce proinflammatory cytokines, leading to chronic inflammation and inhibiting insulin signaling (196,222). The shift from anti-inflammatory Th2 and Treg CD4 ϩ cells toward the proinflammatory Th1 and Th17 CD4 ϩ cells, particularly in the visceral depot, contributes to adipose tissue inflammation associated with insulin resistance (64,163) (Fig. 4).…”

The Role of Adipocyte Hypertrophy and Hypoxia in the Development of Obesity-Associated Adipose Tissue Inflammation and Insulin Resistance

“…Thereby, increased IL-17 secretion by Th17 cells inhibits the differentiation of adipocyte-derived stem cells (ASCs) to adipocytes and also suppresses the insulin responsiveness of the adipocytes. Eljaafari et al [59] provide intriguing evidence by using the co-culture of human ASCs with human mononuclear cells (MNCs), ASCs from obese donors augment the differentiation of naïve CD4 + T cells toward Th17 cells and change the phenotype of MNCs via increased the secretion of IFN-γ by Th17 cells. Taken together, these observations suggest an important role of IL-17 and Th17 cells in obesity-related adipose tissue dysfunction and systemic complications.…”