The global epidemic of obesity is constantly growing and represents an enormous challenge for health care systems worldwide. Obesity fuels the development of metabolic syndrome that includes components such as elevated glucose levels, insulin resistance, elevated blood pressure, and increased levels of triglycerides (1). Obesity and metabolic syndrome increase the risk of metabolic diseases, such as type 2 diabetes (T2D), cardiovascular disease, and atherosclerosis, and contribute to a reduction in life expectancy (2). In the U.S., the obesity rate in adults has reached 36% and obesity affects more than 1 billion people worldwide (3). Currently, 9.3% of the U.S. population has diabetes. In adults, T2D accounts for 90–95% of all diagnosed cases of diabetes, and the estimated total economic burden of diabetes in the U.S. is $245 billion (4). Thus, it is imperative that we increase our understanding of the mechanisms that lead to the development of obesity-induced insulin resistance and T2D, which will help identify therapeutic targets to reduce the impact of these syndromes on morbidity and mortality.
The first piece of evidence that obesity, insulin resistance, and inflammation are interconnected was provided more than a century ago when Dr. R.T. Williamson (5) observed that the anti-inflammatory drug sodium salicylate improved glucose control in patients with diabetes. Almost 90 years later, Hotamisligil et al. (6) revisited this observation as they found that the neutralization of tumor necrosis factor (TNF)-α improved insulin resistance, and thus a link between inflammation and diet-induced insulin resistance was established. Subsequent studies elucidated that a complex immune cellular network regulates inflammation and insulin responsiveness in metabolic tissues. Recently, interleukin (IL)-1β antibodies in monotherapy or in combination with other antidiabetes agents show promise in patients with diabetes (7).
Adipose tissue is a perplexingly complicated endocrine organ that contains a multitude of cell types, such as adipocyte-derived stem cells (ASCs), adipocytes, vascular cells, and immune cells, that all play a role in obesity-induced inflammation. Although the pathogenesis of obesity-induced inflammation and insulin resistance remains incompletely understood, several key events have been identified. Excess calorie intake induces adipose tissue enlargement and causes adipocyte dysfunction. Enlarged adipocytes produce cytokines and chemokines that include TNF-α and chemokine (C-C motif) ligand-2, which, in turn, promote immune cell accumulation in the adipose tissue. Immigrated inflammatory immune cells enhance adipose tissue inflammation, which further exacerbates adipocyte dysfunction. TNF-α secreted by inflammatory cells interferes with insulin receptor signaling pathways in adipocytes and causes peripheral insulin resistance (8). While macrophages are preeminent in promoting proinflammatory conditions in the enlarged adipose tissue (9), recent data confirmed the harmful role of other innate immune cells as well as diverse T-cell subsets, such as CD4+ T helper (Th)1 and CD8+ T effector cells (10). Recently, a role for another Th-cell subset, Th17 cells, in obesity-induced inflammation was implicated based on the findings that the number of Th17 cells increases in obese subjects (11,12) and that IL-17A, the major Th17 cell product, inhibits adipogenesis and therefore promotes insulin resistance (13). The exact mechanisms of Th17 cell development in the enlarged adipose tissue remain unknown.
In this issue of Diabetes, Eljaafari et al. (14) provide intriguing evidence that by coculturing human ASCs with human mononuclear cells (MNCs), ASCs from obese donors, but not from lean donors, drastically change the phenotype of MNCs. First of all, the researchers show that ASCs augment the differentiation of naïve CD4+ T cells toward Th17 cells. In addition to promoting Th17 polarization, ASCs from obese patients inhibit Th1 cell development. Interestingly, the authors found that the presence of ASCs has a dual effect on interferon (IFN)γ secretion based on the IFNγ-producing populations examined: although ASCs inhibited IFNγ production by Th1 cells, they increased the secretion of IFNγ by Th17 cells. This observation brings up the question of by which mechanisms ASCs induce preferential Th17 differentiation over Th1 responses. One possible clue is indicated by the findings that IL-17A secretion was stimulated by both allogeneic and autologous ASCs, which suggests that ASCs might present a specific antigen to T cells to instigate Th17 differentiation. Future studies will clarify the precise mechanisms of how ASCs control CD4+ cell fate in the expanding adipose tissue.
As Eljaafari et al. (14) also found elevated IL-1β and IL-6 production in coculture experiments using ASCs and MNCs, it was important to delineate the cellular origin of these cytokines. As monocytes are the main source of IL-1β and IL-6 production in MNCs, the authors depleted monocytes from MNCs and then they cocultured this depleted fraction of MNCs with ASCs. They observed that monocyte-depleted MNC fractions barely produced IL-1β, while monocyte depletion did not affect IL-6 production, suggesting that monocytes are the main source of IL-1β but not IL-6. Altogether, these results suggest that the triumvirate of monocytes, ASCs, and T cells controls Th17-specific adipose tissue inflammation.
Inflammasomes are caspase-1–containing multicomponent protein complexes, which proteolytically cleave IL-1β and IL-18 to induce the secretion of these cytokines by adipose tissue macrophages (15). Eljaafari et al. (14) reveal that caspase-1 activation and IL-1β secretion are important events in increasing IL-17A production by Th17 cells. While caspase-1 inhibition almost completely abrogated IL-17 production in ASC-MNC coculture experiments, anti–IL-1β antibody–mediated blockade alone only partially decreased IL-17A secretion by Th17 cells. These observations suggest that other inflammasome-regulated factors, including IL-18, also might be needed to trigger optimal IL-17A secretion. In addition, future studies are warranted to identify which specific inflammasome (i.e., NLRP1, NLRP3, NLRC4, and AIM2) is important for IL-17A production and what triggers inflammasome activation in obese adipose tissue. One candidate can be IL-17 itself as it has been shown that IL-17 stimulates IL-1β production by macrophages (16).
Eljaafari et al. (14) also address the molecular signaling mechanisms that lie behind ASC-induced Th17 differentiation. They provide evidence that PI3K and STAT3 are critical factors. Previous studies showed that whereas STAT3 activates IL-17A, STAT5 inhibits IL-17A transcription by binding to the same sites of the IL-17A/F locus (17). The authors of the current study demonstrate that this mechanism is also operational in the adipose tissue, as ASCs favored STAT3 over STAT5 dominancy at the IL-17A/F locus, therefore activating IL-17A transcription. As the authors did not assess what are the mechanisms by which ASCs differentially affect the transcription of IFNγ in Th1 and Th17 cells, this intriguing question will have to be addressed in the future.
In their working model, Eljaafari et al. (14) propose a complex network comprising ASCs, CD4+ T cells, and monocytes (Fig. 1). In this model, ASCs obtained from obese subjects promote Th17 differentiation via increasing the transcription of IL-17A through activating the PI3K and STAT3 pathways. Increased IL-17 secretion by Th17 cells inhibits the differentiation of ASCs to adipocytes and thus the insulin responsiveness of the adipocytes. Furthermore, signals derived from ASCs or MNCs induce inflammasome activation and IL-1β secretion by monocytes, and this secreted IL-1β is required, at least partially, to maintain or further increase IL-17A production by Th17 cells. In summary, this work demonstrates that in addition to the known role of ASCs in affecting the function of Th1 cells (18), ASCs are also active players in regulating Th17-mediated inflammation in the obese adipose tissue. In conclusion, the study by Eljaafari et al. (14) supports the argument that we need to better understand the relationships among the various cell populations that reside in the adipose tissue and their potential contribution to insulin resistance.
See accompanying article, p. 2477.
Duality of Interest. No potential conflicts of interest relevant to this article were reported.