RBP4 Activates Antigen-Presenting Cells, Leading to Adipose Tissue Inflammation and Systemic Insulin Resistance

Abstract

Insulin resistance is a major cause of diabetes and is highly associated with adipose tissue (AT) inflammation in obesity. RBP4, a retinol-transporter, is elevated in insulin resistance and contributes to increased diabetes risk. We aimed to determine the mechanisms for RBP4-induced insulin resistance. Here we show that RBP4 elevation causes AT inflammation by activating innate immunity which elicits an adaptive immune-response. RBP4-overexpressing mice (RBP4-Ox) are insulin-resistant and glucose-intolerant and have increased AT macrophage and CD4 T-cell infiltration. In RBP4-Ox, AT CD206+ macrophages express pro-inflammatory markers and activate CD4 T-cells while maintaining alternatively-activated macrophage markers. These effects result from direct activation of AT antigen-presenting cells (APCs) by RBP4 through a JNK-dependent pathway. Transfer of RBP4-activated APCs into normal mice is sufficient to induce AT inflammation, insulin resistance and glucose intolerance. Thus, RBP4 causes insulin resistance, at least partly, by activating AT APCs which induce CD4 T-cell Th1 polarization and AT inflammation.

Cachexia-associated adipose tissue morphological rearrangement in gastrointestinal cancer patients

“…Disruption in ECM leads to marked metabolic dysregulation and failure to expand AT in both obese patients and experimental obesity (high fat diet and ob/ob knockout) 41. In the same way, AT reduction as induced by a body weight reduction programme was shown to result from modified ECM gene expression profile 42.…”

“…This may be a consequence of an increased lipid scavenging function of ATMϕs, induced by CC. In obesity, a positive relationship between infiltrating ATMϕs and AT remodelling has been demonstrated 41, 47, 48, 49. In particular, CLS are described at sites of adipocyte death.…”

The relationship between circulating irisin, retinol binding protein-4, adiponectin and inflammatory mediators in patients with metabolic syndrome

“…RBP-4 seems to be a cardiometabolic marker in chronic inflammatory diseases including obesity, type 2 diabetes, MetS and CVD. These effects result from the direct activation of antigen presenting cells by RBP-4 (6).…”

Comparison of fractionation strategies for offline two-dimensional liquid chromatography tandem mass spectrometry analysis of proteins from mouse adipose tissue

“…Notably, the following proteins were identified only by the pH-based SCX method: hormone-sensitive lipase (HSL, E9Q4M2), retinol-binding protein 4 (RBP4, H7BW6), cytochrome b5 (Cyb5a, P56395), and the monocarboxylate transporter 1 (Slc16a1, P53986). These proteins play crucial roles in diverse metabolic and hormonal functions of the adipose tissue, and their protein levels are regulated in various obesity-related pathological conditions [42][43][44][45]. Thus, identification of these proteins is of significant interest in proteomics studies addressing adipose tissue function providing additional support for the pH-based SCX elution as a method of choice for these investigations.…”