TIR-Domain-Containing Adaptor-Inducing Interferon-β (TRIF) Is Involved in Glucose Metabolism in Adipose Tissue through the Insulin/AKT Signaling Pathway.

Junling Yang,Ken-Ichiro Fukuchi,Anna Hejmej

doi:10.1155/2020/6942307

Abstract

Obesity significantly increases the risk of developing type 2 diabetes mellitus and other metabolic diseases. Obesity is associated with chronic low-grade inflammation in white adipose tissues, which is thought to play an essential role in developing insulin resistance. Many lines of evidence indicate that toll-like receptors (TLRs) and their downstream signaling pathways are involved in development of chronic low-grade inflammation and insulin resistance, which are associated with obesity. Mice lacking molecules positively involved in the TLR signaling pathways are generally protected from high-fat diet-induced inflammation and insulin resistance. In this study, we have determined the effects of genetic deficiency of toll/interleukin-1 receptor-domain-containing adaptor-inducing interferon-β (TRIF) on food intake, bodyweight, glucose metabolism, adipose tissue macrophage polarization, and insulin signaling in normal chow diet-fed mice to investigate the role of the TRIF-dependent TLR signaling in adipose tissue metabolism and inflammation. TRIF deficiency (TRIF−/−) increased food intake and bodyweight. The significant increase in bodyweight in TRIF−/− mice was discernible as early as 24 weeks of age and sustained thereafter. TRIF−/− mice showed impaired glucose tolerance in glucose tolerance tests, but their insulin tolerance tests were similar to those in TRIF+/+ mice. Although no difference was found in the epididymal adipose mass between the two groups, the percentage of CD206+ M2 macrophages in epididymal adipose tissue decreased in TRIF−/− mice compared with those in TRIF+/+ mice. Furthermore, activation of epididymal adipose AKT in response to insulin stimulation was remarkably diminished in TRIF−/− mice compared with TRIF+/+ mice. Our results indicate that the TRIF-dependent TLR signaling contributes to maintaining insulin/AKT signaling and M2 macrophages in epididymal adipose tissue under a normal chow diet and provide new evidence that TLR4-targeted therapies for type 2 diabetes require caution.

Highlights

Insulin resistance significantly raises the risk of developing metabolic diseases such as type 2 diabetes mellitus (T2DM), hypertension, coronary heart disease, Alzheimer’s disease (AD), and cerebrovascular disease (CVD), as well as certain infectious disease, such as COVID-19 [1,2,3,4,5]
With an exception of TLR3, all toll-like receptors (TLRs) signal through an adaptor, myeloid differentiation factor 88 (MyD88), to activate NF-κB and mitogen-activated protein (MAP) kinases (MyD88dependent pathway), while TLR3 and TLR4 can mediate their signals via an adaptor, toll-interleukin-1 receptor (TIR)-domain-containing adaptor-inducing interferon-β (TRIF), to activate interferon regulatory factor 3 (IRF3) (MyD88-independent/toll/interleukin-1 receptor-domain-containing adaptor-inducing interferon-β (TRIF)-dependent pathway) [12]
We found that TRIF−/− mice were heavier than their wild-type controls. e first significant difference in bodyweight between TRIF−/− and TRIF+/+ mice was discernible at age 24 weeks and, thereafter, the difference was maintained during the experimental period (Figure 1(a), P < 0.05)

Summary

Introduction

Insulin resistance significantly raises the risk of developing metabolic diseases such as type 2 diabetes mellitus (T2DM), hypertension, coronary heart disease, Alzheimer’s disease (AD), and cerebrovascular disease (CVD), as well as certain infectious disease, such as COVID-19 [1,2,3,4,5]. Ese inflammatory changes in visceral adipose tissue have been identified as a major contributor to insulin resistance in obese subjects [7, 8]. Female mice with skeletal musclespecific MyD88 deficiency are protected from inactivityinduced adiposity and insulin resistance [17, 18]. Mice with hepatocyte-specific MyD88 deficiency are prone to develop glucose intolerance, inflammation, and hepatic insulin resistance regardless of bodyweight [19]. TRIF deficiency can prevent development of type 1 diabetes in nonobese diabetic mice by changing the gut microbiota composition and suppression of dendritic cells [20]. Insulin resistance in skeletal muscles from nonobese patients with impaired glucose tolerance is mainly mediated by upregulation of TLR4 due to increased IL-6-mediated STAT3 activation [22]. Mice with TRIF deficiency show glucose intolerance that is associated with pancreatic β-cell dysfunction in vitro [23]

Methods

Results

Conclusion