Abstract
Innate immunity plays a pivotal role in obesity-induced low-grade inflammation originating from adipose tissue. Key receptors of the innate immune system including Toll-like receptors-2 and -4 (TLRs) are triggered by nutrient excess to promote inflammation. The role of other TLRs in this process is largely unknown. In addition to double-stranded viral mRNA, TLR-3 can also recognize mRNA from dying endogenous cells, a process that is frequently observed within obese adipose tissue. Here, we identified profound expression of TLR-3 in adipocytes and investigated its role during diet-induced obesity. Human adipose tissue biopsies (n=80) and an adipocyte cell-line were used to study TLR-3 expression and function. TLR-3-/- and WT animals were exposed to a high-fat diet (HFD) for 16 weeks to induce obesity. Expression of TLR-3 was significantly higher in human adipocytes compared to the non-adipocyte cells part of the adipose tissue. In vitro, TLR-3 expression was induced during differentiation of adipocytes and stimulation of the receptor led to elevated expression of pro-inflammatory cytokines. In vivo, TLR-3 deficiency did not significantly influence HFD-induced obesity, insulin sensitivity or inflammation. In humans, TLR-3 expression in adipose tissue did not correlate with BMI or insulin sensitivity (HOMA-IR). Together, our results demonstrate that TLR-3 is highly expressed in adipocytes and functionally active. However, TLR-3 appears to play a redundant role in obesity-induced inflammation and insulin resistance.
Highlights
Obesity is a worldwide problem that profoundly affects global health [1]
The expression profile of TLR3 was different from the expression pattern observed for the other Toll-like receptors-2 and -4 (TLRs), as it was significantly higher expressed in the mature adipocytes (MA) fraction compared to stromal vascular fraction (SVF) (Fig 1a)
In the current study we examined whether TLR-3-signalling is involved in the development of adipose tissue inflammation and insulin resistance during the development of obesity
Summary
Obesity is a worldwide problem that profoundly affects global health [1]. Obesity is associated with type 2 diabetes mellitus, cardiovascular disease, hepatic steatosis and obesity-related. Adipocytes become hypertrophic and immune cells, such as macrophages [3,4], T- and B-cells [5], infiltrate into the adipose tissue [6]. This inflammatory trait is associated with insulin resistance and subsequently type 2 diabetes mellitus. The role of other TLRs in adipose tissue inflammation remains largely unknown. TLR-3 can bind mRNA that is released from dying cells [18] aside from doublestranded viral mRNA [19], may be activated by apoptotic adipocytes that are frequently observed within obese adipose tissue [20]. We were prompted to investigate the role of TLR-3 in adipose tissue inflammation, using complementary in-vitro and in-vivo experimental models, as well as human adipose tissue biopsies
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