Visceral Adipose Inflammation in Obesity Is Associated with Critical Alterations in Tregulatory Cell Numbers

Abstract

BackgroundThe development of insulin resistance (IR) in mouse models of obesity and type 2 diabetes mellitus (DM) is characterized by progressive accumulation of inflammatory macrophages and subpopulations of T cells in the visceral adipose. Regulatory T cells (Tregs) may play a critical role in modulating tissue inflammation via their interactions with both adaptive and innate immune mechanisms. We hypothesized that an imbalance in Tregs is a critical determinant of adipose inflammation and investigated the role of Tregs in IR/obesity through coordinated studies in mice and humans.Methods and Findings Foxp3-green fluorescent protein (GFP) “knock-in” mice were randomized to a high-fat diet intervention for a duration of 12 weeks to induce DIO/IR. Morbidly obese humans without overt type 2 DM (n = 13) and lean controls (n = 7) were recruited prospectively for assessment of visceral adipose inflammation. DIO resulted in increased CD3+CD4+, and CD3+CD8+ cells in visceral adipose with a striking decrease in visceral adipose Tregs. Treg numbers in visceral adipose inversely correlated with CD11b+CD11c+ adipose tissue macrophages (ATMs). Splenic Treg numbers were increased with up-regulation of homing receptors CXCR3 and CCR7 and marker of activation CD44. In-vitro differentiation assays showed an inhibition of Treg differentiation in response to conditioned media from inflammatory macrophages. Human visceral adipose in morbid obesity was characterized by an increase in CD11c+ ATMs and a decrease in foxp3 expression.ConclusionsOur experiments indicate that obesity in mice and humans results in adipose Treg depletion. These changes appear to occur via reduced local differentiation rather than impaired homing. Our findings implicate a role for Tregs as determinants of adipose inflammation.

Obesity phenotype is related to NLRP3 inflammasome activity and immunological profile of visceral adipose tissue

“…[20,37] and secrete more IL-1β than do CD11c − CD206 + ATMs [20]. As we observed two subsets of ATMs with different caspase-1 activity levels (Fig.…”

“…Changes in NLRP3 and IL1B expression, inflammasome activity and SVCs were not observed in SAT samples between the three phenotypes. So the increase in IL-1β production by the VAT of MUO patients could be explained by a higher number of total ATMs and an increased part of ATMs with a higher caspase-1 [20,37]. However, because obesity and insulin resistance are also associated with increased expression and production of other proinflammatory cytokines, such as TNF-α and IL-6, in adipose tissue [14,38,39], this observed increase in IL-1β production could be also due to a local inflammation in the VAT of MUO patients.…”

Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes

“…Infiltrating lymphocytes precede macrophage populations in obese adipose tissue concomitant with early insulin resistance and may play a role in adipose tissue inflammation by modifying the number and the activation state of adipose tissue macrophages [37][38][39][40]. In mouse models of obesity, an increased numbers of cytotoxic CD8+ effector cells is suspected to initiate the recruitment and activation of adipose tissue macrophages and promote pro-inflammatory cascades associated with insulin resistance [38,40].…”

“…In mouse models of obesity, an increased numbers of cytotoxic CD8+ effector cells is suspected to initiate the recruitment and activation of adipose tissue macrophages and promote pro-inflammatory cascades associated with insulin resistance [38,40]. Obesity also induces modification in the balance between pro-inflammatory (T helper 1 and T helper 17 lymphocytes) and antiinflammatory (T helper 2 and regulatory T lymphocytes) CD4+ cells subsets, leading to secretion of cytokines from newly recruited adipose tissue macrophages [39][40][41]. Of particular interest, the number of anti-inflammatory regulatory T lymphocytes decreases with obesity in adipose tissue of both mice and humans [37,39,40] and even more in obese patients with metabolic syndrome [33].…”

“…Obesity also induces modification in the balance between pro-inflammatory (T helper 1 and T helper 17 lymphocytes) and antiinflammatory (T helper 2 and regulatory T lymphocytes) CD4+ cells subsets, leading to secretion of cytokines from newly recruited adipose tissue macrophages [39][40][41]. Of particular interest, the number of anti-inflammatory regulatory T lymphocytes decreases with obesity in adipose tissue of both mice and humans [37,39,40] and even more in obese patients with metabolic syndrome [33]. The regulatory T lymphocytes express high amount of the antiinflammatory cytokine IL-10 which inhibit macrophage migration and induce the differentiation of M2 macrophages [35,37].…”